title: Two novel mutations in ABHD12: 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.Lys377*) 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. Quantitative reverse transcription-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.
authors.affiliation: Department of Neurology, University of Washington, Seattle, Washington, 98195.
authors.forename: Dong-Hui
authors.initials: DH
authors.lastname: Chen
authors.forename: Alipi
authors.initials: A
authors.lastname: Naydenov
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Blankman
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.forename: Marie
authors.initials: M
authors.lastname: Davis
authors.forename: Youngmee
authors.initials: Y
authors.lastname: Sul
authors.forename: A Samuel
authors.initials: AS
authors.lastname: Barloon
authors.forename: Emily
authors.initials: E
authors.lastname: Bonkowski
authors.forename: John
authors.initials: J
authors.lastname: Wolff
authors.forename: Mark
authors.initials: M
authors.lastname: Matsushita
authors.forename: Corrine
authors.initials: C
authors.lastname: Smith
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Wendy H
authors.initials: WH
authors.lastname: Raskind
authors.forename: Nephi
authors.initials: N
authors.lastname: Stella
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
mesh_terms: D000328:Adult; D001259:Ataxia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D002386:Cataract / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D006579:Heterozygote; D006801:Humans; D008297:Male; D008994:Monoacylglycerol Lipases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011115:Polyneuropathies / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D014158:Transcription, Genetic
chemical_list: C552558:ABHD12 protein, human; D008994:Monoacylglycerol Lipases
keywords: ABHD12; GINS1; PHARC; endocannabinoid; hydrolase activity; short stature
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