Two Novel Mutations in ABHD12 Expand the Mutation Spectrum in PHARC (P05.141)

Abstract

Objective: Genetic study of a patient with progressive Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa, and Cataracts (PHARC). Background PHARC is a recently described autosomal recessive neurodegenerative disease caused by mutations in the anhydrolase domain containing 12 gene (ABHD12) that encodes an enzyme that catalyzes the hydrolysis of 2-arachidonoyl glycerol. Only four homozygous loss-of-function ABHD12 mutations have been reported to date. Design/Methods: We ascertained a 29-year-old woman of Northern European background who manifested the typical features of PHARC. Protein-coding exons of ABHD12 were sequenced in DNA from the patient and her unaffected mother and maternal half-brother. The ABHD12 deletion boundaries were determined by comparative genomic hybridization (CGH) on an array containing 106 oligonucleotide probes with ∼3 kb mean spacing. Quantitative PCR (qPCR) was performed on the patient9s lymphoblastoid line RNA. Results: The patient manifested congenital foot deformities requiring surgery, childhood-onset progressive hearing loss requiring cochlear implants, adolescent-onset cataracts with retinitis pigmentosa and macular edema, and a demyelinating motor/sensory peripheral neuropathy. Her brain MRI was normal. In addition, she and her unaffected mother both have short stature, 4911, whereas her unaffected maternal half-brother has normal height. Sequencing of ABHD12 in the patient identified a novel 1129a→t (Lys377X) mutation in exon 12. Targeted CGH detected a 59 kb deletion that encompassed exon 1 of ABHD12 and exons 1-4 of an adjacent gene, GINS1, and includes the promoters of both genes. The deletion was found in the mother but not in the maternal half-brother. RNA qPCR revealed remarkably decreased expression of ABHD12 in the patient. Conclusions: We report a fifth ABHD12 mutation and the first instance of compound heterozygosity in PHARC. The mutations severely reduce ABHD12 expression; effect on hydrolase activity is under investigation. The possible involvement of haploinsufficiency for GINS1, a DNA replication complex protein, in the short stature of the patient and her mother requires further study. Supported by: The Department of Veterans Affairs and R01 NS069719-01. Disclosure: Dr. Chen has received license fee payments from Athena Diagnostics. Dr. Davis has nothing to disclose. Dr. Mefford has nothing to disclose. Dr. Sul has nothing to disclose. Dr. Naydenov has nothing to disclose. Dr. Barloon has nothing to disclose. Dr. Wolff has nothing to disclose. Dr. Matsushita has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Stella has nothing to disclose. Dr. Raskind has received (royalty or license fee or contractual rights) payments from Athena Diagnostics. Dr. Bird has received personal compensation for activities with Athena Diagnostics for speakers bureau and licensing fees.Dr. Bird has received liscensing payments from Athena Diagnostics.