title: Molecular genetics of FAM161A in North American patients with early-onset retinitis pigmentosa.
abstract: Retinitis pigmentosa (RP) is a hereditary disease that leads to the progressive degeneration of retinal photoreceptor cells and to blindness. It is caused by mutations in several distinct genes, including the ciliary gene FAM161A, which is associated with a recessive form of this disorder. Recent investigations have revealed that defects in FAM161A represent a rather prevalent cause of hereditary blindness in Israel and the Palestinian territories, whereas they seem to be rarely present within patients from Germany. Genetic or clinical data are currently not available for other countries. In this work, we screened a cohort of patients with recessive RP from North America to determine the frequency of FAM161A mutations in this ethnically-mixed population and to assess the phenotype of positive cases. Out of 273 unrelated patients, only 3 subjects had defects in FAM161A. A fourth positive patient, the sister of one of these index cases, was also identified following pedigree analysis. They were all homozygous for the p.T452Sfx3 mutation, which was previously reported as a founder DNA variant in the Israeli and Palestinian populations. Analysis of cultured lymphoblasts from patients revealed that mutant FAM161A transcripts were actively degraded by nonsense-mediated mRNA decay. Electroretinographic testing showed 30 Hz cone flicker responses in the range of 0.10 to 0.60 microvolts in all cases at their first visit (age 12 to 23) (lower norm  =  50 μV) and of 0.06 to 0.32 microvolts at their most recent examination (age 27 to 43), revealing an early-onset of this progressive disease. Our data indicate that mutations in FAM161A are responsible for 1% of recessive RP cases in North America, similar to the prevalence detected in Germany and unlike the data from Israel and the Palestinian territories. We also show that, at the molecular level, the disease is likely caused by FAM161A protein deficiency.
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Giulia
authors.initials: G
authors.lastname: Venturini
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Silvio Alessandro
authors.initials: SA
authors.lastname: Di Gioia
authors.affiliation: The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America.
authors.forename: Shyana
authors.initials: S
authors.lastname: Harper
authors.affiliation: The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America.
authors.forename: Carol
authors.initials: C
authors.lastname: Weigel-DiFranco
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rivolta
authors.affiliation: The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America.
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Berson
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D017398:Alternative Splicing; D016022:Case-Control Studies; D002648:Child; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D059365:Nonsense Mediated mRNA Decay; D009656:North America / Q000453:epidemiology; D009898:Optic Disk / Q000473:pathology; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D005136:Eye Proteins; C552553:FAM161A protein, human