Communicated by Ming Qi
Two Novel Mutations in ABHD12: Expansion of the Mutation Spectrum in PHARC and Assessment of Their Functional Effects
Article first published online: 2 OCT 2013
© 2013 WILEY PERIODICALS, INC.
Volume 34, Issue 12, pages 1672–1678, December 2013
How to Cite
Chen, D.-H., Naydenov, A., Blankman, J. L., Mefford, H. C., Davis, M., Sul, Y., Barloon, A. S., Bonkowski, E., Wolff, J., Matsushita, M., Smith, C., Cravatt, B. F., Mackie, K., Raskind, W. H., Stella, N. and Bird, T. D. (2013), Two Novel Mutations in ABHD12: Expansion of the Mutation Spectrum in PHARC and Assessment of Their Functional Effects. Hum. Mutat., 34: 1672–1678. doi: 10.1002/humu.22437
Contract grant sponsors: NIH R01 NS069719, DA033747, DA021696, DA011322, DA017259, DA009789, and DA026430; Burroughs Wellcome Fund Career Award; and funds from Department of Veterans Affairs.
- Issue published online: 13 NOV 2013
- Article first published online: 2 OCT 2013
- Accepted manuscript online: 11 SEP 2013 07:44AM EST
- Manuscript Accepted: 25 AUG 2013
- Manuscript Received: 10 MAY 2013
- Burroughs Wellcome Fund Career Award. Grant Numbers: NIH R01 NS069719, DA033747, DA021696, DA011322, DA017259, DA009789, DA026430
- Department of Veterans Affairs
- short stature;
- hydrolase activity
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.