title: A truncating mutation in SERPINB6 is associated with autosomal-recessive nonsyndromic sensorineural hearing loss.
abstract: More than 270 million people worldwide have hearing loss that affects normal communication. Although astonishing progress has been made in the identification of more than 50 genes for deafness during the past decade, the majority of deafness genes are yet to be identified. In this study, we mapped a previously unknown autosomal-recessive nonsyndromic sensorineural hearing loss locus (DFNB91) to chromosome 6p25 in a consanguineous Turkish family. The degree of hearing loss was moderate to severe in affected individuals. We subsequently identified a nonsense mutation (p.E245X) in SERPINB6, which is located within the linkage interval for DFNB91 and encodes for an intracellular protease inhibitor. The p.E245X mutation cosegregated in the family as a completely penetrant autosomal-recessive trait and was absent in 300 Turkish controls. The mRNA expression of SERPINB6 was reduced and production of protein was absent in the peripheral leukocytes of homozygotes, suggesting that the hearing loss is due to loss of function of SERPINB6. We also demonstrated that SERPINB6 was expressed primarily in the inner ear hair cells. We propose that SERPINB6 plays an important role in the inner ear in the protection against leakage of lysosomal content during stress and that loss of this protection results in cell death and sensorineural hearing loss.
authors.affiliation: Dr. John T. Macdonald Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Asli
authors.initials: A
authors.lastname: Sirmaci
authors.forename: Seyra
authors.initials: S
authors.lastname: Erbek
authors.forename: Justin
authors.initials: J
authors.lastname: Price
authors.forename: Mingqian
authors.initials: M
authors.lastname: Huang
authors.forename: Duygu
authors.initials: D
authors.lastname: Duman
authors.forename: F Başak
authors.initials: FB
authors.lastname: Cengiz
authors.forename: Güney
authors.initials: G
authors.lastname: Bademci
authors.forename: Suna
authors.initials: S
authors.lastname: Tokgöz-Yilmaz
authors.forename: Burcu
authors.initials: B
authors.lastname: Hişmi
authors.forename: Hilal
authors.initials: H
authors.lastname: Ozdağ
authors.forename: Banu
authors.initials: B
authors.lastname: Oztürk
authors.forename: Sevsen
authors.initials: S
authors.lastname: Kulaksizoğlu
authors.forename: Erkan
authors.initials: E
authors.lastname: Yildirim
authors.forename: Haris
authors.initials: H
authors.lastname: Kokotas
authors.forename: Maria
authors.initials: M
authors.lastname: Grigoriadou
authors.forename: Michael B
authors.initials: MB
authors.lastname: Petersen
authors.forename: Hashem
authors.initials: H
authors.lastname: Shahin
authors.forename: Moien
authors.initials: M
authors.lastname: Kanaan
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Zheng-Yi
authors.initials: ZY
authors.lastname: Chen
authors.forename: Susan H
authors.initials: SH
authors.lastname: Blanton
authors.forename: Xue Z
authors.initials: XZ
authors.lastname: Liu
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.forename: Nejat
authors.initials: N
authors.lastname: Akar
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
mesh_terms: D018389:Codon, Nonsense; D003241:Consanguinity; D005190:Family; D034381:Hearing Loss / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D040941:Heredity; D006720:Homozygote; D006801:Humans; D009154:Mutation; D015843:Serpins / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D015843:Serpins; C094472:serpin B6
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