Two Novel Mutations inABHD12: Expansion of the Mutation Spectrum in PHARC and Assessment of Their Functional Effects

Abstract

PHARC (Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa, and Cataracts) is a recently described autosomal recessive neurodegenerative disease caused by mutations in the α–β–hydrolase domain-containing 12 gene (ABHD12). Only five homozygous ABHD12 mutations have been reported and the pathogenesis of PHARC remains unclear. We evaluated a woman who manifested short stature as well as the typical features of PHARC. Sequence analysis of ABHD12 revealed a novel heterozygous c.1129A>T (p.Lys377X) mutation. Targeted comparative genomic hybridization detected a 59 kb deletion that encompasses exon 1 of ABHD12 and exons 1–4 of an adjacent gene, GINS1, and includes the promoters of both genes. The heterozygous deletion was also carried by the patient’s asymptomatic mother. qRT-PCR demonstrated ~50% decreased expression of ABHD12 RNA in lymphoblastoid cell lines from both individuals. Activity-based protein profiling of serine hydrolases revealed absence of ABHD12 hydrolase activity in the patient and 50% reduction in her mother. This is the first report of compound heterozygosity in PHARC and the first study to describe how a mutation might affect ABHD12 expression and function. The possible involvement of haploinsufficiency for GINS1, a DNA replication complex protein, in the short stature of the patient and her mother requires further studies.

In vivo metabolite profiling as a means to identify uncharacterized lipase function: Recent success stories within the alpha beta hydrolase domain (ABHD) enzyme family

“…Like ABHD6, ABHD12 had previously been shown to hydrolyze the endocannabinoid lipid 2-arachidonylglycerol in vitro [28–30], but true physiologically relevant substrates had not been identified until the elegant recent work of Blankman and colleagues [31]. Prior to this important study, mutations in ABHD12 had been shown to be the cause of a neurodegenerative disease called polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract (PHARC) in humans [32–34]. It was originally thought ABHD12’s enzymatic ability to hydrolyze 2-arachidonylglycerol may contribute to the development of PHARC, but a recent metabolic profiling study has identified a novel role for ABHD12 acting as a lysophospholipase to regulate the progression of PHARC [31].…”

A complex homozygous mutation in ABHD12 responsible for PHARC syndrome discovered with NGS and review of the literature

“…Only 14 mutations in ABHD12 have been reported to date (Fig. ), including 4 nonsense, 2 large deletions, 3 frameshifts, leading to a stop codon, 4 missense, and 1 splicing mutation among 33 patients from 18 families and 9 countries (Fiskerstrand et al, ; Eisenberger et al, ; Chen et al, ; Nishiguchi et al, ; Yoshimura et al, ; Tingaud‐Sequeira et al, ) . We report a large complex homozygous indel mutation, leading to a frameshift and a stop codon in exon 3: p.Asn127Aspfs*23.…”

“…). These 15 mutations are organized into 12 different genotypes: 9 homozygous and 3 compound heterozygous (Fiskerstrand et al, ; Eisenberger et al, ; Chen et al, ; Nishiguchi et al, ; Yoshimura et al, ; Tingaud‐Sequeira et al, ) .…”

“…Deafness was often progressive and varied from moderate to profound. Five patients were successfully fitted with cochlear implants (Eisenberger et al, ; Chen et al, ; Yoshimura et al, ; Tingaud‐Sequeira et al, ) . The first ophthalmological symptom that appeared was cataract, occurring at a mean age of 25 years (min: 8 years; max: 45 years) followed by retinitis pigmentosa at a mean age of 29 years (min: 16 years; max: 46 years).…”

“…A review of the literature retrieved 11 other distinct genotypes presented in 6 articles (Fiskerstrand et al, ; Eisenberger et al, ; Chen et al, ; Nishiguchi et al, ; Yoshimura et al, ; Tingaud‐Sequeira et al, ) . PHARC syndrome is generally a slowly progressive disease, with the occurrence of the first symptoms during adolescence.…”