Genetic insights into PHARC syndrome: identification of a novel frameshift mutation in ABHD12
ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
Eye Research Centre, Five Senses Health Institute, School of Medicine, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
Stem Cell and Regenerative Medicine Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
Pediatric Growth and Development Research Center, Institute of Endocrinology and metabolism, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
Abstract
Background
Mutations in ABHD12 (OMIM: 613,599) are associated with polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) syndrome (OMIM: 612674), which is a rare autosomal recessive neurodegenerative disease. PHARC syndrome is easily misdiagnosed as other neurologic disorders, such as retinitis pigmentosa, Charcot-Marie-Tooth disease, and Refsum disease, due to phenotype variability and slow progression. This paper presents a novel mutation in ABHD12 in two affected siblings with PHARC syndrome phenotypes. In addition, we summarize genotype-phenotype information of the previously reported patients with ABHD12 mutation.
Methods
Following a thorough medical evaluation, whole-exome sequencing was done on the proband to look for potential genetic causes. This was followed by confirmation of identified variant in the proband and segregation analysis in the family by Sanger sequencing. The variants were interpreted based on the American College of Medical Genetics and Genomics (ACMG) guidelines.
Results
A novel pathogenic homozygous frameshift variant, NM_001042472.3:c.601dup, p.(Val201GlyfsTer4), was identified in exon 6 of ABHD12 (ACMG criteria: PVS1 and PM2, PM1, PM4, PP3, and PP4). Through Sanger sequencing, we showed that this variant is co-segregated with the disease in the family. Further medical evaluations confirmed the compatibility of the patients’ phenotype with PHARC syndrome.
Conclusions
Our findings expand the spectrum of mutations in the ABHD12 and emphasize the significance of multidisciplinary diagnostic collaboration among clinicians and geneticists to solve the differential diagnosis of related disorders. Moreover, a summary based on mutations found so far in the ABHD12 gene did not suggest a clear genotype-phenotype correlation for PHARC syndrome.
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Keywords: Hearing loss, Polyneuropathy, Retinitis pigmentosa, Ataxia, Cataract, PHARC, Neurodegenerative, ABHD12, Whole-exome sequencing, Endocannabinoid
Article notes
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Received 2023 Apr 8; Accepted 2023 Oct 2; Collection date 2023.
Introduction
Concurrent impairments of the essential senses of hearing and vision greatly influence affected individuals’ quality of life and often result in morbidity and mortality [1–4]. This accompaniment accounts for nearly 0.015% of the general population, with patients under 18 years of age making up 5.7% of this group [5]. Among diverse etiological reasons for these impairments, heritable factors are estimated to be responsible for 27% of cases [5]. Usher syndrome has the highest frequency among such impairments [5, 6]; other syndromes include PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract) syndrome (OMIM: 612674), Heimler syndrome 1 (OMIM: 234580), Alstrom syndrome (OMIM: 203800), Bardet-Biedel syndrome (OMIM: 209900), and Cone-rod dystrophy and hearing loss 1 (OMIM: 617236).
PHARC syndrome is an autosomal recessive neurodegenerative disease influencing the peripheral and central nervous systems. Its name is taken from its significant features, including polyneuropathy, hearing loss, ataxia, retinitis pigmentosa (RP), and cataract [7], although not all of these features necessarily manifest at the initial presentation [7, 8]. Some patients show only some of these symptoms for years so affected individuals are usually misdiagnosed with other neurodegenerative diseases like Usher syndrome, RP, Refsum, Charcot-Marie-Tooth, and mitochondrial diseases [8, 9]. Genetic testing can lead to a definitive diagnosis by differentiating between these similar syndromes.
Loss of function mutations in the ABDH12 gene (OMIM: 613599) cause PHARC syndrome. This gene contains 13 coding exons on chromosome 20 and translates to an α/βhydrolase domain-containing 12 (ABHD12) protein. The ABHD12 protein is a kind of enzyme that participates in lipid metabolism by catalyzing 2-arachidonoyl glycerol (2-AG) [7]. 2-AG, as the main endocannabinoid lipid transmitter, acts in neuroinflammation and synaptic plasticity. The endocannabinoid system participates in different biological processes, for instance, neurotransmission, inflammation, mood, appetite, pain appreciation, and addiction behavior [10]. ABHD12 is expressed in different mouse tissues, but the highest expression has been observed in microglia and macrophages, especially in the brain [7]. Since a single functional copy of ABHD12 makes sufficient enzyme activity therefore, heterozygous carriers do not present any clinical features [11, 12].
The current challenge of diagnosing PHARC syndrome makes it essential to investigate its clinical and genetic features. Increasing data in these areas can expand the current knowledge about its onset, the existence of genotype-phenotype correlations, and the natural history of PHARC syndrome; it may also help introduce new potential treatment strategies.
This report presents the clinical manifestation of two affected individuals from a consanguineous Iranian family with mild sensory symptoms, progressive hearing impairment, cataract, and RP. Whole-exome sequencing (WES), followed by segregation analysis, confirmed a novel biallelic mutation in ABHD12. We also compared the clinical presentation and molecular findings of these patients with the previous reports of PHARC syndrome to gain a better realization of the genotype-phenotype correlations of ABHD12.
Methods
Study participants and clinical evaluations
In this study, two Iranian consanguineous siblings with mild sensory symptoms, progressive hearing impairment, RP, and cataract were enlisted (Fig. 1a). The proband (IV.1) was a 25-year-old male; his 18-year-old sister (IV.2) had the same manifestation but with milder symptoms. Clinical examinations, involving family history and physical exams, were conducted in Hazrat Rasoul Akram Hospital, Tehran, Iran. The patients (IV.1 and IV.2) were examined by otologists, ophthalmologists, and neurologists.
Standard conventional audiometry, including air- and bone-conduction testing, was carried out for IV.1, IV.2, III.1, and III.2 [13]. Additionally, a complete ophthalmologic examination of the afflicted individuals (IV.1 and IV.2) included assessments of best-corrected visual acuity (BCVA), slit lamp bio microscopy, electroretinography (ERG), and optic coherence tomography (OCT). Neurological evaluations include electromyographic recordings, nerve conduction studies comprising measurements of motor and sensory nerves of the upper and lower extremities, and magnetic resonance brain imaging (MRI). Routine laboratory testing was conducted, including tests for liver transaminases, glomerular filtration rate, complete blood count, and electrolytes. Genomic DNA was extracted from blood samples (5 mL) of patients and healthy parents as described before [14].
Whole-exome sequencing and bioinformatics analysis
WES was done based on the previous works [15, 16]. Briefly, the exomes were captured by the SureSelect Human All Exon V7 Kit (Agilent, Santa Clara, CA, USA). Sequencing was done on an Illumina Hiseq2000 system (Illumina, San Diego, USA) with a mean coverage of 100X. The GRCh38/hg38 genome assembly was used to align reads.
To reach the disease-causing variants, firstly, the variants with minor allele frequency above 1% in databases like bSNP [17], gnomAD [18], and Iranome [19] were removed from the WES data of the patient. Secondly, synonymous changes and all non-coding areas other than the 20 bp flanking regions were eliminated. Bioinformatics techniques such as SIFT [20], Polyphen2 [21], MutationTaster [22], PROVEAN [23], and Combined Annotation Dependent Depletion [24] were used to predict the outcomes of the variants. According to patients’ clinical manifestations (e.g., sensorimotor neuropathy, hearing impairment, and abnormal eye physiology), the remaining variations were prioritized using ClinVar [25], Human Gene Mutation Database (HGMD) [26], human phenotype ontology [27], and Deafness Variation Database (DVD) [28]. Variant interpretation followed the ACMG/AMP (American College of Genetics and Genomics/Association for Molecular Pathology) recommendations [2].
Family segregation study and protein analysis
Direct Sanger sequencing was used to verify the identified variants in affected members, and co-segregation analysis of the causative homozygous variant was done on all family members. The primers for the area of interest were designed using Primer3 software [29]. The forward primer: 5′-GTCTTTGTCAGGACCCAGGA-3′ and the reverse primer: 5′-AGTCAGGCAGCATGTCACAG-3′ were used to amplify the identified variant in ABHD12. PCR was done in standard conditions [15]. The PCR products were used for direct Sanger sequencing and the data were analyzed using Codon code aligner V.5.1.5.
To study the effect of identified mutation on the ABHD12 functional domains ConSurf server (https://consurf.tau.ac.il/) and UniProt [30] were used. Swiss-Model software (https://swissmodel.expasy.org/interactive) was used to design the 3D structure of the protein. I-Mutant3.0 was used to predict protein stability (http://gpcr2.biocomp.unibo.it/cgi/predictors/I-Mutant3.0/I-Mutant3.0.cgi), and MetaDome [31] was used to recognize the intolerant areas in the ABHD12 protein.
Literature review
In November 2022, a thorough search was conducted in Google Scholar and PubMed using the terms ABHD12 and PHARC syndrome. All original English full-text articles and case reports with clinical and genetic information were added. Available phenotype and genotype were included.
Results
Clinical findings
The patients were born to a first-cousin marriage (Fig. 1a). Both patients presented bilateral pes cavus. Audiology evaluations showed a progressive sensorineural hearing impairment in patients (IV.1 and IV.2) that was first distinguished at the age of 11. The audio profiles of patients at different ages are shown in (Fig. 1d, e), and air conduction audiograms of their healthy parents are presented in (Fig. 1b,c).
A physical examination of IV.1 indicated mild symptoms of stance ataxia with positive Romberg and tandem gait signs, while IV.2 was normal. Heel-to-shin and finger-to-nose tests were normal in both patients, and sensory deficits in the sensation of temperature, vibration, and touch could not be found. Furthermore, both patients’ tendon reflexes in the upper and lower extremities were normal, and muscular atrophy and weakness were absent. Routine laboratory tests were normal in both patients.
Electrophysiology
Both patients’ nerve conduction studies revealed a chronic demyelinating sensorimotor neuropathy with uniform conduction, showing that nerve conduction velocities were well below 40 m/s in both the upper and lower extremities.
Electromyographic recordings in both patients displayed a regular pattern of the motor unit. Pathologic spontaneous activity could not be found.
Ophthalmologic examination and brain imaging
An ophthalmologic examination revealed that BCVA was 2/10 and 2/10 for IV.1 and 9/10 and 8/10 for IV.2 for the right and left eyes, respectively. Patient IV.1 showed a bilateral moderate posterior subcapsular cataract, while his younger sister (IV.2) showed a bilateral mild posterior subcapsular cataract. Both patients showed signs of RP in fundus autofluorescence (FAF), OCT, and ERG (Fig. 2and Fig. 3). The MRI of the brain of patient IV.1 revealed cerebellar atrophy (Fig. 4), while it was normal in patient IV.2.
Molecular findings
Four family members were evaluated in total (Fig. 1a). Firstly, based on the ACMG guidelines for screening for genes associated with hearing loss [2], the absence of mutation in GJB2 was investigated in both patients (IV.1 and IV.2) [32, 33]. After the analysis of the exome sequencing data on IV.1 (Fig. 5b), a novel frameshift duplication in exon six of the ABHD12 gene—NM_001042472.3: c.601 dup; p.(Val201GlyfsTer4)— that co-segregated with the phenotype was identified (Figs. 1a and 5a). The variant was not reported in ClinVar, DVD, HGMD, dbSNP v.154, and gnomAD. The allele frequency for this variant was zero in Iranome (local database).
This variant is located in the αβ-hydrolase domain of the ABHD12 protein (Fig. 6a). We further confirmed this finding by using I-Mutant3.0, which exhibited that this variant can bring the protein close to an unstable (Free Energy change value < − 3.03) and predict its effect on human health (Disease RI: 5). Actually, the I-mutant server calculates the free energy of mutant protein and negative value of free energy change shows a decrease in protein stability. The MetaDome (a server for analysis the mutation tolerance at each position in a human protein) results indicated that this variant was situated in the intolerant regions of the ABHD12 protein (Fig. 6b).
We classified the novel frameshift based on ACMG/AMP guidelines (Criteria: PVS1 and PM2, PM1, PM4, PP3, and PP4) as “pathogenic” variant [2].
Literature review
A comprehensive analysis of ABHD12 variants was carried out. Data from this research were compared with 14 previously published articles [7–9, 11, 12, 34–42]. In summary, 58 patients from 38 families were included. 29 distinct ABHD12 mutations have been identified in these published articles. Their phenotype, genotype, age, and sex are summarized in (Table 1), while all variants are illustrated in Fig. 6. It has been documented that ABHD12 exhibits a broad range of clinical heterogeneity in terms of age of onset, spectrum of phenotypes, severity, and progression. Cataract and hearing impairment were the most common conditions reported in ABHD12 patients.
| Nucleotide change* | AA change | E I | Mutation type | Age Sex | Poly neuropathy | Motor Neuropathy | HL | RP | ERG | Cataract | Ataxia | MR CT | Pyramidal Tract Signs | Other | Country | Family case | Ref |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 14 kb deletion removing exon 1 | E1 | Deletion | 24 M | Abnormal | Pes cavus; absent tendon reflexes | 14y Deaf | 20y | NR | 15y | Mild | Normal | Indifferent plantar response | No | UAE | 6.1 | [7] | |
| 14 kb deletion removing exon 1 | E1 | Deletion | 20 M | Demyelinating polyneuropathy | Pes cavus; absent tendon reflexes | 6y | Yes | NR | Yes | Speech and limb ataxia; wheelchair-bound (10y) | Cerebellar atrophy 3y | Extensor plantar response | No | UAE | 6.2 | [7] | |
| 14 kb deletion removing exon 1 | E1 | Deletion | 6 F | NR | Absent tendon reflexes | Yes | No | NR | Yes | Speech and limb | Cerebellar atrophy | Indifferent plantar response | No | UAE | 6.3 | [7] | |
| c.193 C > T | p.Arg65* | E2 | Nonsense | 55 F | No | No | 17y35y CI | Yes | Rod-cone abnormal | Yes | Ataxic gait with poor tandem walking; action tremor with writing cramp and involuntary athetotic movements of her fingers | Normal | NR | Night blindness, glaucoma | Lebanese | II.1 | [41] |
| c.193 C > T | p.Arg65* | E2 | Nonsense | 53 M | NR | NR | 24y35y CI | Yes | NR | Posterior subcapsular cataract | NR | NR | NR | Glaucoma; severe optic atrophy | Lebanese | II.4 | [41] |
| c.193 C > T | p.Arg65* | E2 | Nonsense | 22 M | Yes | 7y; Lack of coordination | No | Yes | Rod-cone dystrophy | No | NR | NR | NR | No | NR | ABHD12-3 H-10 | [34][8] |
| c.211-223del | p.Arg71Tyrfs*26 | E2 | Frameshift | 42 M | Demyelinating polyneuropathy | Pes cavus; hammertoes; sensory loss; | 43y bilaterally CI | Yes | Rod-cone dystrophy | 38y | Wide-base gait, action tremor in the upper limbs | Mild cerebellar atrophy | NR | muscle MRI revealed mild fatty infiltration in the intrinsic muscles of both feet and the anterior compartment of the left leg | Spanish | II.3 | [37] |
| c.211-223del | p.Arg71Tyrfs*26 | E2 | Frameshift | NR M | Demyelinating polyneuropathy | Pes cavus; hammertoes; sensory loss | 18y | Yes | NR | Yes | Wide-base gait; dysarthria; slight dysmetria | Mild cerebellar atrophy | NR | No | Spanish | II.1 | [37] |
| c.249 C > G | p.Tyr83* | E2 | Nonsense | 41 M | NR | NR | 32y progressive | Yes | Abnormal | Yes | NR | NR | NR | Olfactory decline | China | I.1 | [36] |
| c.249 C > G | p.Tyr83* | E2 | Nonsense | 31 M | NR | NR | 32y progressive | Yes | NR | Yes | NR | NR | NR | Olfactory decline | China | II.5 | [36] |
| c.259 C > Ac.1063 C > T | p. Pro87Thrp.Arg355* | E2E12 | MissenseNonsense | 28 F | NR | NR | No | Yes | Rod-cone dystrophy | No | No | NR | NR | No | NR | ABHD12-2 | [34] |
| c.316 + 2T > A | I2 | Splice site | 56 M | Yes | Sensory loss | 15y 41y CI | 22y | NR | Yes | Steppage gait | Normal | NR | No | Japan | KTM 5012 | [39] | |
| c.316 + 2T > A | I2 | Splice site | 64 M | NR | NR | Progressive | 45y | NR | Yes | NR | Cerebral and cerebellar atrophy | NR | Epilepsy; 30y night blindness | Japan | SNS5547 | [39] | |
| c.316 + 2T > A | I2 | Splice site | NR M | NR | NR | Deaf | Yes | NR | Yes | NR | NR | NR | Epilepsy | Japan | SNS5548 | [39] | |
| c.319delAc.605 C > T | p.Arg107Glufs*8p.Thr202Ile | E3E6 | FrameshiftMissense | 78 F | No | Decreased vibration sense in lower limbs | Presbycusis | Yes | NR | Yes | No | Minimal cerebral atrophy | No | No | Spain | 1292-II.4 | [40] |
| c.319delAc.605 C > T | p.Arg107Glufs*8p.Thr202Ile | E3E6 | FrameshiftMissense | 75 M | No | Slightly loss of strength right upper limb | Presbycusis | Yes | NR | Yes | Dysmetria in lower limbs; slightly wide basegait | Normal | No | No | Spain | 1292-II.5 | [40] |
| c.319delAc.605 C > T | p.Arg107Glufs*8p.Thr202Ile | E3E6 | FrameshiftMissense | 72 F | No | No | NR | Yes | NR | Yes | Gait somewhat unstable | NR | No | No | Spain | 1292-II.6 | [40] |
| c.319delAc.605 C > T | p.Arg107Glufs*8p.Thr202Ile | E3E6 | FrameshiftMissense | 66 M | No | No | Presbycusis | Yes | Diminished | Yes | Slight dysarthria; mild distal postural tremor | Normal | No | No | Spain | 1292-II.7 | [40] |
| c.337-338delGAinsTTT | p.Asp113Phefs*15 | E3 | Frameshift | 62 F | Demyelinating polyneuropathy | 38y; pes cavus; sensory loss; absent ankle reflexes | 20y | 38y | Rod-cone dystrophy | 28y | No | Normal | No | No | Norway | 1.1 | [7] |
| c.337-338delGAinsTTT | p.Asp113Phefs*15 | E3 | Frameshift | 56 M | Demyelinating polyneuropathy | 37y; pes cavus | 30y | 37y | Rod-cone dystrophy | 37y | 37y; gait ataxia | Normal | Extensor plantar response at lower limbs; spasticity; hyperreflexia | No | Norway | 1.2 | [7] |
| c.337-338delGAinsTTT | p.Asp113Phefs*15 | E3 | Frameshift | 46 M | Demyelinating polyneuropathy | 38y; distal sensory loss | Yes | 46y | Rod-cone dystrophy | 25y | 43y; gait ataxia; upper limb intention tremor | Cerebellar atrophy | Extensor plantar response at lower limbs; spasticity; hyperreflexia | No | Norway | 1.3 | [7] |
| c.337-338delGAinsTTT | p.Asp113Phefs*15 | E3 | Frameshift | 58 M | Demyelinating/ axonal polyneuropathy | 51y; pes cavus; sensory loss; reduced tendon reflexes | 20y | 35y | Rod-cone dystrophy | 26y | No | Cerebellar atrophy | Extensor plantar response at lower limbs | No | Norway | 2.1 | [7] |
| c.337-338delGAinsTTT | p.Asp113Phefs*15 | E3 | Frameshift | 54 F | Yes | 53y; pes cavus; reducedtendon reflexes | 20y | 25y | Flat | 25y | No | NR | No | NO | Norway | 2.2 | [7] |
| c.337-338delGAinsTTT | p.Asp113Phefs*15 | E3 | Frameshift | 36 F | Demyelinating polyneuropathy | Pes cavus; reduced tendon reflexes in lower limbs | 10y Deaf | 36y | Rod-cone dystrophy | 32y | Yes | Atrophy of vermis and medulla oblongata | Extensor plantar response at right side; spasticity | No | Norway | 3.1 | [7] |
| c.337-338delGAinsTTT | p.Asp113Phefs*15 | E3 | Frameshift | 24 M | Demyelinating polyneuropathy | Pes cavus; hammertoes; reduced tendon reflexes in upper and lower limbs | Yes | No | Normal | 15y | No | Slight ventricular asymmetry | Indifferent plantar response | No | Norway | 4.1 | [7] |
| c.337-338delGAinsTTT | p.Asp113Phefs*15 | E3 | Frameshift | 16 M | Demyelinating polyneuropathy | Pes cavus; reduced sensibility; reduced tendon reflexes in upper limbs, absent in lower limbs | 13y | No | Normal | 16y slight | No | Normal | No | No | Norway | 5.1 | [7] |
| c.337-338delGAinsTTT | p.Asp113Phefs*15 | E3 | Frameshift | 20 M | Yes | NR | 16y | Yes | NR | Star-shaped cataract 17y | No | Cerebellar atrophy | NR | No | NR | J-12 | [8] |
| c.337-338delGAinsTTT | p.Asp113Phefs*15 | E3 | Frameshift | 17 M | Yes | NR | 10y | Yes | NR | Star-shaped cataract 10y | No | Cerebellar atrophy | NR | No | NR | J-13 | [8] |
| c.337-338delGAinsTTT | p.Asp113Phefs*15 | E3 | Frameshift | 36 F | NR | NR | 12y | Yes | Rod-cone dystrophy | Posterior subcapsular cataract 32y | Yes | NR | NR | No | NR | E-7 | [8] |
| c.337-338delGAinsTTT | p.Asp113Phefs*15 | E3 | Frameshift | 32 F | Yes | NR | 17y | Yes | Rod-cone dystrophy | Posterior subcapsular cataract 32y | 45y | NR | NR | No | NR | B-2 | [8] |
| c.337-338delGAinsTTTc.341dup | p.Asp113Phefs*15p.Leu114Phefs*14 | E3E3 | FrameshiftFrameshift | 39 M | NR | NR | 33y | Yes | Rod-cone dystrophy | Star-shaped cataract 29y | NR | NR | NR | No | NR | L-15 | [8] |
| c.337-338delGAinsTTTc.423-1_425del | p.Asp113Phefs*15p.(?) | E3I3 | FrameshiftSplice site | 33 M | Yes | Subtle foot drop; absent Achilles tendon reflexes | No | Yes | NR | Sutural cataract 3y | 27y | Normal | NR | No | NR | C-3 | [8] |
| c.337-338delGAinsTTTc.423-1_425del | p.Asp113Phefs*15p.(?) | E3I3 | FrameshiftSplice site | 33 M | Yes | Distal muscle weakness; sensory loss | Yes | Yes | Sutural cataract 3y | 27y | Normal | NR | No | NR | C-4 | [8] | |
| c.337-338delGAinsTTTc.423-1_425del | p.Asp113Phefs*15p.(?) | E3I3 | FrameshiftSplice site | 38 M | Yes | Abnormal gait pattern; distal sensory loss | 20y | Yes | Star-shaped cataract 4y | 31y | Cerebellar atrophy | NR | No | NR | C-5 | [8] | |
| c.337-338delGAinsTTTc.1075del | p.Asp113Phefs*15p.Val359Phefs*27 | E3E12 | FrameshiftFrameshift | 47 M | Yes | Pes cavus, hammertoes, distal sensory loss, absent tendon reflexes 8y | 28y | Yes | Rod-cone dystrophy | 36y | 8y | Normal | NR | No | NR | A-1 | [8] |
| c.374 C > Tc.1154T > C | p.Thr125Metp.Leu385Pro | E3E12 | MissenseMissense | 53 M | NR | NR | 44y progressive | Yes | NR | Posterior polar cataract 41y | NR | NR | NR | Epilepsy; learning difficulties | NR | ABHD12-5I-11 | (8, 34) |
| c.379-385del AACTACT insGATTCCTTATATACCATTGTAGTCTTACTGCTTTTGGTGAACACA | p.Asn127Aspfs*23 | E3 | Deletion-Insertion | 36 M | Demyelinating polyneuropathy | Yes | 5y Deaf | No | NR | 28y | 15y ataxic walk | Normal | NR | No | France | XIX.1 | [12] |
| c.447G > Ac.557G > C | p.Trp159*p.Arg186Pro | E4E5 | NonsenseMissense | 30 M | Yes | Distal sensory loss; reduced tendon reflexes | Yes | Yes | Rod-cone dystrophy | Cortical cataract | Wide-based gait; Stuttering speech; ataxic gait | Normal | No | No | Netherlands | W08-1833D-6 | (8, 40) |
| c.601dup | p.Val201Glyfs*4 | E6 | Frameshift | 25 M | Yes | Pes cavus; slight gait disturbance | Yes | Yes | Abnormal | Yes | Yes | Cerebellar atrophy | No | No | Iran | IV.1 | This study |
| c.601dup | p.Val201Glyfs*4 | E6 | Frameshift | 18 F | Yes | Pes cavus | Yes | Yes | Abnormal | Yes | No | Normal | No | No | Iran | IV.2 | This study |
| c.620–2 A > G | I6 | Splice site | 34 M | Yes | 31y; Lower limb muscle weakness | 20y progressive | Yes | Rod-cone dystrophy | 26y | No | NR | NR | No | NR | ABHD12-4G-9 | (8, 34) | |
| c.758 C > G | p.Thr253Arg | E8 | Missense | 31 F | Demyelinating polyneuropathy | Sensory loss | 31y bilateral CI | Yes | NR | Posterior subcapsular cataract8y | ataxia 16y; mild intentional tremor; mild dysarthria; wheelchair-bound | Normal | NR | Decreased function of the labyrinths | Swedish | II.1 | [38] |
| c.784 C > Tc.867 + 5G > A | p.Arg262* | E8I9 | NonsenseSplice site | 53 M | Yes | 53y; Distal sensory loss | 20y progressive | Yes | NR | No | No | NR | NR | No | NR | ABHD12-6 F-8 | (8, 34) |
| c.784 C > T | p.Arg262* | E8 | Nonsense | 21 M | Demyelinating polyneuropathy | Pes cavus: reduced tendon reflexes at upper and lower limbs | 9y 17y CI | No | NR | Yes | Stance ataxia | Cerebellar atrophy | No | No | Iraq | A | [35] |
| c.784 C > T | p.Arg262* | E8 | Nonsense | 25 M | Demyelinating polyneuropathy | Sensory loss; Loss of Achilles and patellar tendon reflexes | 12y 18y CI | Yes | NR | Yes | Slight bilateral limb ataxia | NR | NR | No | Iraq | B | [35] |
| c.846-852dupTAAGAGC | p.His285fs*1 | E9 | Frameshift | 11 M | Yes | Absent tendon reflexes; moderate muscle weakness at lower limbs | No | No | NR | No | 3-4y; limb ataxia; horizontal nystagmus; dysarthria; dysmetria delayed walking at 15 months; action and intention tremor | Cerebellar atrophy | Extensor planter response at lower limbs | No | Algeria | 8.1 | [7] |
| c.846-852dupTAAGAGC | p.His285fs*1 | E9 | Frameshift | 10 F | Yes | Absent tendon reflexes at lower limbs | No | No | NR | No | 4-5y; gait ataxia | Vermian atrophy | Extensor planter response at lower limbs | No | Algeria | 8.2 | [7] |
| c.846-852dupTAAGAGC | p.His285fs*1 | E9 | Frameshift | 44 M | Demyelinating polyneuropathy | Pes cavus; sensory loss; absent tendon reflexes at lower limbs; scoliosis | Yes | Amblyopia | NR | NR | 7-10y limb ataxia; dysarthria; dysmetria at upper limbs with adiadocokinesia; head titubation | Vermian atrophy | Extensor planter response at lower limbs; macroglossia | No | Algeria | 9.1 | [7] |
| c.846-852dupTAAGAGC | p.His285fs*1 | E9 | Frameshift | 26 F | Demyelinating polyneuropathy | Pes cavus; sensory loss; reduced tendon reflexes at upper limbs, and absent at lower limbs; tongue fasciculation | Deaf | Yes | NR | Yes | 4-9y gait and limb ataxia; horizontal nystagmus; moderate dysarthria; dysmetria at upper and lower limbs | Vermian atrophy | Extensor planter response at lower limbs; | No | Algeria | 9.2 | [7] |
| c.846-852dupTAAGAGC | p.His285fs*1 | E9 | Frameshift | 26 F | Severe demyelinating polyneuropathy on nerve biopsy | Pes cavus; sensory loss; absent tendon reflexes | 6y | No | NR | No | 6-12y limb ataxia | Normal | Indifferent plantar response | No | Algeria | 10.1 | [7] |
| c.846-852dupTAAGAGC | p.His285fs*1 | E9 | Frameshift | 19 F | Yes | 12y; pes cavus; sensory loss; absent tendon reflexes at upper and lower limbs | NR | NR | NR | NR | No | NR | NR | No | Algeria | 10.2 | [7] |
| c.846-852dupTAAGAGC | p.His285fs*1 | E9 | Frameshift | 32 F | Axonal polyneuropathy | Pes cavus; sensory loss;absent tendon reflexes at lower limbs | Yes | Decreased visual acuity and amblyopia | NR | No | 16-20y; gait ataxia; dysarthria; dysmetria at upper limbs | Cerebellar atrophy | Extensor plantar response at lower limbs | No | Algeria | 11.1 | [7] |
| c.846-852dupTAAGAGC | p.His285fs*1 | E9 | Frameshift | 23 F | Yes | NR | Yes | Yes | NR | Yes | Yes | NR | NR | No | Spain | 10 | [42] |
| c.1054 C > T | p.Arg352* | E12 | Nonsense | 50 F | Abnormal | 34y; pes cavus; hammertoes; | 17y | 20y | NR | 22y | 18y; dysarthria; gait ataxia; jerky eye movementtremor in hand | Cerebellar atrophy Increased signal in periventricular white matter | Flexor planter response; spasticity; | No | USA | 7.1 | [7] |
| c.1054 C > T | p.Arg352* | E12 | Nonsense | 29 F | Demyelinating polyneuropathy | Pes cavus; sensory loss; absent tendon reflexes; a mild waddling | 16y | Yes | NR | Yes | Gait ataxia; progressive jerky tremor; mild titubation of the trunk; mild proximal tetraparesis; dysmetria; mild bilateral ptosis; congenital convergent strabismus | Global moderate cerebral/cerebellar atrophy | NR | Mild learning disabilities | Portugal | [9] | |
| c.1054 C > T c.1196del | p.Arg352*p.*399Serfs*122 | E12E13 | Nonsense | 48 F | NR | NR | No | yes | No Rod-cone dystrophy | Yes | No | NR | NR | No | NR | ABHD12-1 | [34] |
| c.1063 C > T | p.Arg355* | E12 | Nonsense | 46 F | Yes | NR | Yes | Yes | Rod-cone dystrophy | Cerulean cataract | Yes | NR | NR | NR | K-14 | [8] | |
| c.1116 C > G | p.His372Gln | E12 | Missense | 38 F | Demyelinating polyneuropathy | Distal symmetric hypoesthesia to touch and pain; achilles reflex abolished | 38y | Yes | Diminished | Yes | No | Cerebral and cerebellar atrophy | NR | No | Spain | RP-1487 | [40] |
| c.1129 A > T59 Kb deletion including exon 1 | p.Lys377* | E12E1 | NonsenseDeletion | 29 F | Demyelinating polyneuropathy | Pes cavus; sensory loss; absent tendon reflexes | HL from Childhood 21y bilateral CI | Yes | Abnormal | Yes | Steppage gait; mild dysmetria | Normal | Flexor plantar response | No | Japan | III.1 | [11] |
Most mutations reported in ABHD12 were frameshift mutations (Table 1). The c.337-338delGAinsTTT is the most common variant. only seven of these variants (c.193 C > T, c.316 + 2T > A, c.337-338delGAinsTTT, c.784 C > T, c.846-852dupTAAGAGC, c.1054 C > T, and c.1063 C > T) have been reported in more than one family.
Discussion
In this study, we detected a novel frameshift variant in the ABHD12 gene in two affected Iranian siblings with PHARC syndrome from a first-cousin marriage (Fig. 1a). The identified variant, c.601dup; p.(Val201GlyfsTer4), leads to a premature stop codon (Fig. 5c), which can result in a loss of function, and was determined as a pathogenic variant in agreement with ACMG guidelines [2].
PHARC syndrome is distinguished by hearing impairment, polyneuropathy, RP, ataxia, and early-onset cataract. The variety of clinical symptoms showed that ABHD12 play crucial roles in the in the central and peripheral nervous systems, as well as the eye, which is confirmed by its expression patterns [7]. ABHD12 is expressed ubiquitously and is extremely expressed in the brain, especially in microglia, macrophages, and in the retina [7, 43].
ABHD12 was detected on chromosome 20 (20p11.21) for the first time in 2010. 29 mutations in 58 patients (38 families) from 14 previously published articles related to the PHARC syndrome around the world have been introduced (Table 1; Fig. 6a). These patients exhibited clinical variability concerning the spectrum of phenotypes, disease onset, severity, and progression [7, 8], and this variability was observed both within the same family and between patients with the same variant from different families (Table 1) [8, 37]. In addition, there is no correlation between the location and type of mutation and the severity of phenotypes in patients. For example, in a comparison between two nonsense mutations (p.Arg352* and p.Arg65*), the patients with the first mutation in early adulthood showed complete phenotypes of PHARC syndrome, while the patients with the second mutation did not experience neuropathy until the fifth decade of their lives (Table 1) [41]. The current evidence does not indicate any genotype-phenotype correlation in patients with mutations in the ABHD12 gene. However, the limited number of reported cases, the multisystemic nature of the PHARC syndrome (which leads to misdiagnosis or delayed diagnosis), delayed referral for evaluation of related phenotypes, or failure to record all phenotypes at the same time in different studies can be effective.
This study’s proband (IV.1) manifested a typical PHARC phenotype, the onset of which dates to the patient’s early teenage years. It had a progressive nature, eventually revealing hearing impairment, bilateral posterior subcapsular cataract, ataxia, demyelinating polyneuropathy, and RP. The clinical picture was completely compatible with PHARC syndrome when the patient was 24 years old. The progression of the disease in the second affected family member was the same, though the symptoms were milder.
In line with most previous studies, sensorineural hearing impairment was the first manifestation in both patients (Table 1). Figure 1 indicates the progress of hearing impairment in both patients. Both patients developed posterior subcapsular cataract during childhood, corroborating previous reports showing that posterior subcapsular cataract frequently occurs in RP patients at a young age [44]. Similar to previous studies, our patients’ definitive diagnosis of PHARC syndrome after a long follow-up period was possible only using WES [7, 8, 35]. The multisystemic nature and slow progression of PHARC syndrome is the main reason for its misdiagnosis. Performing genetic testing next to clinical findings could lead to early diagnosis, timely referrals, and better management of future symptoms.
The ABHD12 gene encodes a 398-amino acid protein product that participates in endocannabinoid metabolism and synaptic plasticity. This product is called the ABHD12 protein, which is a member of the serine hydrolase family and inactivates the endocannabinoid neurotransmitter 2-AG [35, 38]. Furthermore, previous in vivo studies indicated the lysophosphatidylserine (LPS) lipase activity of Abhd12 in the mouse brain and the accumulation of LPS in the mouse model. This accumulation increases phagocytosis activity and microglial activation, which causes neuroinflammation and atrophy in the cerebellum. This neuroinflammation is the presumed cause of motor and auditory defects over time [45–47].
ABHD12 is a single-pass integral membrane protein with a transmembrane helix in the N-terminal region and an extracellular active site domain in the C-terminal region [48]. The αβ-hydrolase domain of ABHD12 consists of a lipase motif and catalytic triad (predicted amino acid residues S246-D333-H372), which serves as a fully conserved structure in both humans and rodents [49]. This domain expands between residues 165–351 of ABHD12 (Fig. 6) [36]. The p.(Val201GlyfsTer4) variant occurs within the conserved αβ-hydrolase domain and causes a premature stop codon, which may result in nonsense-mediated decay and, consequently, a lack of the protein product. Navia-Paldanius et al. have shown that site-directed mutagenesis of residues of the catalytic triad of the αβ-hydrolase domain abolished the enzymatic activity of ABHD12 [49]. The research group of Tingaud-Sequeira et al. with functional studies on p.R352* mutation that produces a truncated protein have proved the loss of enzyme activity [38]. Moreover, the variants in this domain are likely to disturb interactions with other molecules or other parts of the protein and affect protein function [38].
ABHD12 is a critical protein in the signaling, metabolism, and regulation of lipids, especially in immune and neurological processes [8, 38, 45, 47].
However, further research is required to fully understand the cellular, molecular, and biochemical mechanisms through which ABHD12 contributes to the PHARC syndrome. Such research could lead to earlier diagnosis, appropriate referrals, effective prognosis for future rehabilitations, improved medical management of disease progression, better genetic counseling, and prevention strategies, and a higher increasing quality of life for patients and their relatives.
A significant limitation in this research pertains to the inability to perform a functional analysis that would elucidate the specific contribution of the newly identified variant to PHARC syndrome.
Conclusion
We elucidated the role of a novel pathogenic mutation in the ABHD12 as a genetic reason of PHARC syndrome in an Iranian family. Additionally, we demonstrated the value of using WES for the early diagnosis of this syndrome. Our findings extend the mutation spectrum of ABHD12 by introducing a novel mutation. We also summarized previously reported mutations in the ABHD12 gene throughout the world and compared them to the new mutation investigated in the present study. We believe these results can help practitioners identify disease pathology and manage the phenotypes in a multidisciplinary setting.
Acknowledgements
We are so grateful to the family members for their collaboration in this study.
Abbreviations
- PHARC
- polyneuropathy hearing loss ataxia retinitis pigmentosa cataracts
- RP
- Retinitis pigmentosa
- ABHD12
- α/βhydrolase domain-containing 12
- 2-AG
- 2-arachidonoyl glycerol
- WES
- whole-exome sequencing
- BCVA
- best-corrected visual acuity
- ERG
- electroretinography
- OCT
- optic coherence tomography
- MRI
- magnetic resonance brain imaging
- Val
- valine
- Gly
- glycine
- ACMG/AMP
- American College of Medical Genetics/Association for Molecular Pathology
Funding
This work was supported by Iran University of Medical Sciences, Tehran, Iran (Grant Number: 1400-2-22-21218). The funding bodies played no role in the study design, data collection and analysis, decision to publish and writing of the manuscript.
Data Availability
The datasets produced during this manuscript are available from the corresponding author upon reasonable request. The novel variant and phenotypes were submitted in ClinVar database (accession number: VCV001727244.1) and available at (https://www.ncbi.nlm.nih.gov/clinvar/variation/1727244/).
Declarations
Ethics approval and consent to participate
The study was conducted in accordance to the guidelines of the Declaration of Helsinki, and approved by the ethics committee of Iran University of Medical Sciences (Tehran, Iran). (Approval number: IR.IUMS.REC.1400.862). Informed consent was obtained from all subjects and/or their legal guardian(s).
Consent for publication
Written informed consent for publication of clinical details and clinical images was obtained from the legal guardians.
Competing interests
The authors declare no competing interests.
Footnotes
Footnote Group
References
Untitled section
References
- 1.Lam BL, Lee DJ, Gómez-Marín O, Zheng DD, Caban AJ. Concurrent visual and hearing impairment and risk of mortality: the National Health interview survey. Archives of Ophthalmology (Chicago Ill: 1960) 2006;124(1):95–101. doi: 10.1001/archopht.124.1.95.
- 2.Oza AM, DiStefano MT, Hemphill SE, Cushman BJ, Grant AR, Siegert RK, et al. Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. Hum Mutat. 2018;39(11):1593–613. doi: 10.1002/humu.23630.
- 3.Chia E-M, Mitchell P, Rochtchina E, Foran S, Golding M, Wang JJJA. Association between vision and hearing impairments and their combined effects on quality of life. 2006;124(10):1465–70.
- 4.Liljas AE, Wannamethee SG, Whincup PH, Papacosta O, Walters K, Iliffe S et al. Socio-demographic characteristics, lifestyle factors and burden of morbidity associated with self-reported hearing and vision impairments in older british community-dwelling men: a cross-sectional study. 2016;38(2):e21–e8.
- 5.Wittich W, Watanabe DH, Gagné JP. Sensory and demographic characteristics of deafblindness rehabilitation clients in Montréal. Can Ophthalmic Physiological Optics: J Br Coll Ophthalmic Opticians (Optometrists) 2012;32(3):242–51. doi: 10.1111/j.1475-1313.2012.00897.x.
- 6.Kimberling WJ, Hildebrand MS, Shearer AE, Jensen ML, Halder JA, Trzupek K, et al. Frequency of Usher syndrome in two pediatric populations: implications for genetic screening of deaf and hard of hearing children. Genet Medicine: Official J Am Coll Med Genet. 2010;12(8):512–6. doi: 10.1097/GIM.0b013e3181e5afb8.
- 7.Fiskerstrand T, H’Mida-Ben Brahim D, Johansson S, M’Zahem A, Haukanes BI, Drouot N, et al. Mutations in ABHD12 cause the neurodegenerative disease PHARC: an inborn error of endocannabinoid metabolism. Am J Hum Genet. 2010;87(3):410–7. doi: 10.1016/j.ajhg.2010.08.002.
- 8.Nguyen XT, Almushattat H, Strubbe I, Georgiou M, Li CHZ, van Schooneveld MJ et al. The phenotypic spectrum of patients with PHARC Syndrome due to Variants in ABHD12: an Ophthalmic Perspective. Genes. 2021;12(9).
- 9.Dias Bastos PA, Mendonça M, Lampreia T, Magriço M, Oliveira J, Barbosa R. PHARC Syndrome, a Rare Genetic disorder-case report. Mov Disorders Clin Pract. 2021;8(6):977–9. doi: 10.1002/mdc3.13266.
- 10.Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3):389–462. doi: 10.1124/pr.58.3.2.
- 11.Chen DH, Naydenov A, Blankman JL, Mefford HC, Davis M, Sul Y, et al. Two novel mutations in ABHD12: expansion of the mutation spectrum in PHARC and assessment of their functional effects. Hum Mutat. 2013;34(12):1672–8. doi: 10.1002/humu.22437.
- 12.Lerat J, Cintas P, Beauvais-Dzugan H, Magdelaine C, Sturtz F, Lia AS. A complex homozygous mutation in ABHD12 responsible for PHARC syndrome discovered with NGS and review of the literature. J Peripheral Nerv System: JPNS. 2017;22(2):77–84. doi: 10.1111/jns.12216.
- 13.Falah M, Farhadi M, Kamrava SK, Mahmoudian S, Daneshi A, Balali M, et al. Association of genetic variations in the mitochondrial DNA control region with presbycusis. Clin Interv Aging. 2017;12:459–65. doi: 10.2147/CIA.S123278.
- 14.Falah M, Houshmand M, Mahmoudian S, Emamdjomeh H, Ghavami Y, Farhadi M. The anticipation and inheritance pattern of c.487A > G mutation in the GJB2 gene. Arch Iran Med. 2012;15(1):49–51.
- 15.Rayat S, Farhadi M, Emamdjomeh H, Morovvati S, Falah M. Analysis of TMIE gene mutations including the first large deletion of exon 1 with autosomal recessive non-syndromic deafness. BMC Med Genom. 2022;15(1):133. doi: 10.1186/s12920-022-01287-9.
- 16.Vafaee-Shahi M, Farhadi M, Razmara E, Morovvati S, Ghasemi S, Abedini SS et al. Novel phenotype and genotype spectrum of NARS2 and literature review of previous mutations. Ir J Med Sci. 2021.
- 17.Smigielski EM, Sirotkin K, Ward M, Sherry ST. dbSNP: a database of single nucleotide polymorphisms. Nucleic Acids Res. 2000;28(1):352–5. doi: 10.1093/nar/28.1.352.
- 18.Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–43. doi: 10.1038/s41586-020-2308-7.
- 19.Fattahi Z, Beheshtian M, Mohseni M, Poustchi H, Sellars E, Nezhadi SH, et al. Iranome: a catalog of genomic variations in the iranian population. Hum Mutat. 2019;40(11):1968–84. doi: 10.1002/humu.23880.
- 20.Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012;40(Web Server issue):W452–7.
- 21.Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248–9. doi: 10.1038/nmeth0410-248.
- 22.Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11(4):361–2. doi: 10.1038/nmeth.2890.
- 23.Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinf (Oxford England) 2015;31(16):2745–7. doi: 10.1093/bioinformatics/btv195.
- 24.Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47(D1):D886–d94. doi: 10.1093/nar/gky1016.
- 25.Landrum MJ, Chitipiralla S, Brown GR, Chen C, Gu B, Hart J, et al. ClinVar: improvements to accessing data. Nucleic Acids Res. 2020;48(D1):D835–d44. doi: 10.1093/nar/gkz972.
- 26.Stenson PD, Ball EV, Mort M, Phillips AD, Shaw K, Cooper DN. The human gene mutation database (HGMD) and its exploitation in the fields of personalized genomics and molecular evolution. Curr Protocols Bioinf. 2012;Chap. 1:Unit1.13.
- 27.Köhler S, Vasilevsky NA, Engelstad M, Foster E, McMurry J, Aymé S, et al. The human phenotype ontology in 2017. Nucleic Acids Res. 2017;45(D1):D865–d76. doi: 10.1093/nar/gkw1039.
- 28.Azaiez H, Booth KT, Ephraim SS, Crone B, Black-Ziegelbein EA, Marini RJ, et al. Genomic Landscape and Mutational Signatures of Deafness-Associated genes. Am J Hum Genet. 2018;103(4):484–97. doi: 10.1016/j.ajhg.2018.08.006.
- 29.Kõressaar T, Lepamets M, Kaplinski L, Raime K, Andreson R, Remm M. Primer3_masker: integrating masking of template sequence with primer design software. Bioinf (Oxford England) 2018;34(11):1937–8. doi: 10.1093/bioinformatics/bty036.
- 30.UniProt The Universal protein knowledgebase in 2023. Nucleic Acids Res. 2023;51(D1):D523–d31. doi: 10.1093/nar/gkac1052.
- 31.Wiel L, Baakman C, Gilissen D, Veltman JA, Vriend G, Gilissen C, MetaDome Pathogenicity analysis of genetic variants through aggregation of homologous human protein domains. Hum Mutat. 2019;40(8):1030–8. doi: 10.1002/humu.23798.
- 32.Falah M, Houshmand M, Akbaroghli S, Mahmodian S, Ghavami Y, Farhadi M. Profile of iranian GJB2 mutations in young population with novel mutation. J Iran J Basic Med Sci. 2011;14(3):213–8.
- 33.Falah M, Houshmand M, Balali M, Asghari A, Bagher Z, Alizadeh R, et al. Role of GJB2 and GJB6 in iranian nonsyndromic hearing impairment: from Molecular Analysis to Literature Reviews. Fetal Pediatr Pathol. 2020;39(1):1–12. doi: 10.1080/15513815.2019.1627625.
- 34.Igelman AD, Ku C, da Palma MM, Georgiou M, Schiff ER, Lam BL, et al. Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome. Ophthalmic Genet. 2021;42(6):664–73. doi: 10.1080/13816810.2021.1946704.
- 35.Thimm A, Rahal A, Schoen U, Abicht A, Klebe S, Kleinschnitz C, et al. Genotype-phenotype correlation in a novel ABHD12 mutation underlying PHARC syndrome. J Peripheral Nerv System: JPNS. 2020;25(2):112–6. doi: 10.1111/jns.12367.
- 36.Li T, Feng Y, Liu Y, He C, Liu J, Chen H, et al. A novel ABHD12 nonsense variant in Usher syndrome type 3 family with genotype-phenotype spectrum review. Gene. 2019;704:113–20. doi: 10.1016/j.gene.2019.04.008.
- 37.Frasquet M, Lupo V, Chumillas MJ, Vázquez-Costa JF, Espinós C, Sevilla T. Phenotypical features of two patients diagnosed with PHARC syndrome and carriers of a new homozygous mutation in the ABHD12 gene. J Neurol Sci. 2018;387:134–8. doi: 10.1016/j.jns.2018.02.021.
- 38.Tingaud-Sequeira A, Raldúa D, Lavie J, Mathieu G, Bordier M, Knoll-Gellida A, et al. Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC. Neurobiol Dis. 2017;98:36–51. doi: 10.1016/j.nbd.2016.11.008.
- 39.Yoshimura H, Hashimoto T, Murata T, Fukushima K, Sugaya A, Nishio SY et al. Novel ABHD12 mutations in PHARC patients: the differential diagnosis of deaf-blindness. The Annals of otology, rhinology, and laryngology. 2015;124 Suppl 1:77s-83s.
- 40.Nishiguchi KM, Avila-Fernandez A, van Huet RA, Corton M, Pérez-Carro R, Martín-Garrido E, et al. Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration. Ophthalmology. 2014;121(8):1620–7. doi: 10.1016/j.ophtha.2014.02.008.
- 41.Eisenberger T, Slim R, Mansour A, Nauck M, Nürnberg G, Nürnberg P, et al. Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3. Orphanet J Rare Dis. 2012;7:59. doi: 10.1186/1750-1172-7-59.
- 42.Corriols-Noval P, López Simón EC, Cadiñanos J, Diñeiro M, Capín R, González Aguado R et al. Clinical Impact of Genetic Diagnosis of Sensorineural Hearing Loss in Adults. Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 2022;43(10):1125-36.
- 43.Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. New York, NY: Science; 2015. p. 1260419.
- 44.Chatterjee S, Agrawal D, Agrawal D, Parchand SM, Sahu A. Cataract surgery in retinitis pigmentosa. Indian J Ophthalmol. 2021;69(7):1753–7. doi: 10.4103/ijo.IJO_2916_20.
- 45.Blankman JL, Long JZ, Trauger SA, Siuzdak G, Cravatt BF. ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC. Proc Natl Acad Sci USA. 2013;110(4):1500–5. doi: 10.1073/pnas.1217121110.
- 46.Ogasawara D, Ichu TA, Vartabedian VF, Benthuysen J, Jing H, Reed A, et al. Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo. Nat Chem Biol. 2018;14(12):1099–108. doi: 10.1038/s41589-018-0155-8.
- 47.Singh S, Kamat SS. The loss of enzymatic activity of the PHARC-associated lipase ABHD12 results in increased phagocytosis that causes neuroinflammation. Eur J Neurosci. 2021;54(10):7442–57. doi: 10.1111/ejn.15516.
- 48.Savinainen JR, Saario SM, Laitinen JT. The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors. Acta Physiologica (Oxford England) 2012;204(2):267–76. doi: 10.1111/j.1748-1716.2011.02280.x.
- 49.Navia-Paldanius D, Savinainen JR, Laitinen JT. Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12) J Lipid Res. 2012;53(11):2413–24. doi: 10.1194/jlr.M030411.
Associated Data
Data Availability Statement
The datasets produced during this manuscript are available from the corresponding author upon reasonable request. The novel variant and phenotypes were submitted in ClinVar database (accession number: VCV001727244.1) and available at (https://www.ncbi.nlm.nih.gov/clinvar/variation/1727244/).