title: Homozygosity mapping reveals null mutations in FAM161A as a cause of autosomal-recessive retinitis pigmentosa.
abstract: Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerations caused by mutations in at least 45 genes. Using homozygosity mapping, we identified a ∼4 Mb homozygous region on chromosome 2p15 in patients with autosomal-recessive RP (arRP). This region partially overlaps with RP28, a previously identified arRP locus. Sequence analysis of 12 candidate genes revealed three null mutations in FAM161A in 20 families. RT-PCR analysis in 21 human tissues revealed high levels of FAM161A expression in the retina and lower levels in the brain and testis. In the human retina, we identified two alternatively spliced transcripts with an intact open reading frame, the major one lacking a highly conserved exon. During mouse embryonic development, low levels of Fam161a transcripts were detected throughout the optic cup. After birth, Fam161a expression was elevated and confined to the photoreceptor layer. FAM161A encodes a protein of unknown function that is moderately conserved in mammals. Clinical manifestations of patients with FAM161A mutations varied but were largely within the spectrum associated with arRP. On funduscopy, pallor of the optic discs and attenuation of blood vessels were common, but bone-spicule-like pigmentation was often mild or lacking. Most patients had nonrecordable electroretinographic responses and constriction of visual fields upon diagnosis. Our data suggest a pivotal role for FAM161A in photoreceptors and reveal that FAM161A loss-of-function mutations are a major cause of arRP, accounting for ∼12% of arRP families in our cohort of patients from Israel and the Palestinian territories.
authors: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Dikla
authors: D
authors: Bandah-Rozenfeld
authors: Liliana
authors: L
authors: Mizrahi-Meissonnier
authors: Chen
authors: C
authors: Farhy
authors: Alexey
authors: A
authors: Obolensky
authors: Itay
authors: I
authors: Chowers
authors: Jacob
authors: J
authors: Pe'er
authors: Saul
authors: S
authors: Merin
authors: Tamar
authors: T
authors: Ben-Yosef
authors: Ruth
authors: R
authors: Ashery-Padan
authors: Eyal
authors: E
authors: Banin
authors: Dror
authors: D
authors: Sharon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D019143:Evolution, Molecular; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005190:Family; D005654:Fundus Oculi; D018507:Gene Expression Regulation, Developmental; D005808:Genes, Recessive / Q000235:genetics*; D006720:Homozygote; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D005136:Eye Proteins; C552553:FAM161A protein, human; C552554:Fam161A protein, mouse