title: 3p-- syndrome defines a hearing loss locus in 3p25.3.
abstract: Deletions affecting the terminal end of chromosome 3p result in a characteristic set of clinical features termed 3p-- syndrome. Bilateral, sensorineural hearing loss (SNHL) has been found in some but not all cases, suggesting the possibility that it is due to loss of a critical gene in band 3p25. To date, no genetic locus in this region has been shown to cause human hearing loss. However, the ATP2B2 gene is located in 3p25.3, and haploinsufficiency of the mouse homolog results in SNHL with similar severity. We compared auditory test results with fine deletion mapping in seven previously unreported 3p-- syndrome patients and identified a 1.38Mb region in 3p25.3 in which deletions were associated with moderate to severe, bilateral SNHL. This novel hearing loss locus contains 18 genes, including ATP2B2. ATP2B2 encodes the plasma membrane calcium pump PMCA2. We used immunohistochemistry in human cochlear sections to show that PMCA2 is located in the stereocilia of hair cells, suggesting its function in the auditory system is conserved between humans and mice. Although other genes in this region remain candidates, we conclude that haploinsufficiency of ATP2B2 is the most likely cause of SNHL in 3p-- syndrome.
authors.affiliation: The Virginia Merrill Bloedel Hearing Research Center and the Department of Otolaryngology-Head and Neck Surgery, University of Washington School of Medicine, Box 357923, Seattle, WA 98195, USA. brenmcc@u.washington.edu
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: McCullough
authors.forename: Joe C
authors.initials: JC
authors.lastname: Adams
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Shilling
authors.forename: M Patrick
authors.initials: MP
authors.lastname: Feeney
authors.forename: Kathleen C Y
authors.initials: KC
authors.lastname: Sie
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Tempel
mesh_terms: D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D003051:Cochlea / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006312:Hearing Loss, Bilateral / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009154:Mutation; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013577:Syndrome
chemical_list: D017931:DNA Primers; D053499:Plasma Membrane Calcium-Transporting ATPases; C506958:ATP2B2 protein, human; C506959:Atp2b2 protein, mouse