Two Novel Mutations inABHD12: Expansion of the Mutation Spectrum in PHARC and Assessment of Their Functional Effects
| Autor: | Wendy H. Raskind, Youngmee Sul, Heather C Mefford, Ken Mackie, Benjamin F. Cravatt, Marie Y. Davis, John Wolff, Nephi Stella, Alipi Naydenov, Dong Hui Chen, Jacqueline L. Blankman, Emily Bonkowski, Mark Matsushita, A. Samuel Barloon, Corrine O. Smith, Thomas D. Bird |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Heterozygote Ataxia Transcription Genetic Gene Expression Biology Compound heterozygosity medicine.disease_cause Cataract Article Polyneuropathies Exon Gene Order Gene expression Retinitis pigmentosa Genetics medicine Humans Gene Genetics (clinical) Sequence Deletion Mutation medicine.disease Molecular biology Monoacylglycerol Lipases Pedigree Phenotype Female medicine.symptom Haploinsufficiency Retinitis Pigmentosa |
| Zdroj: | Human Mutation. 34:1672-1678 |
| ISSN: | 1059-7794 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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