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Two Novel Mutations in ABHD 12 : Expansion of the Mutation Spectrum in PHARC and Assessment of Their Functional Effects
Author(s) -
Chen DongHui,
Naydenov Alipi,
Blankman Jacqueline L.,
Mefford Heather C.,
Davis Marie,
Sul Youngmee,
Barloon A. Samuel,
Bonkowski Emily,
Wolff John,
Matsushita Mark,
Smith Corrine,
Cravatt Benjamin F.,
Mackie Ken,
Raskind Wendy H.,
Stella Nephi,
Bird Thomas D.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22437
Subject(s) - biology , haploinsufficiency , genetics , exon , compound heterozygosity , retinitis pigmentosa , mutation , frameshift mutation , gene , microbiology and biotechnology , trinucleotide repeat expansion , phenotype , allele
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 ( ABHD 12 ). Only five homozygous ABHD 12 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 ABHD 12 revealed a novel heterozygous c.1129 A > T (p. L ys377*) mutation. Targeted comparative genomic hybridization detected a 59‐kb deletion that encompasses exon 1 of ABHD 12 and exons 1–4 of an adjacent gene, GINS 1 , 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 ABHD 12 RNA in lymphoblastoid cell lines from both individuals. Activity‐based protein profiling of serine hydrolases revealed absence of ABHD 12 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 ABHD 12 expression and function. The possible involvement of haploinsufficiency for GINS 1, a DNA replication complex protein, in the short stature of the patient and her mother requires further studies.