title: Whole Exome Sequencing Identified MCM2 as a Novel Causative Gene for Autosomal Dominant Nonsyndromic Deafness in a Chinese Family.
abstract: We report the genetic analysis of autosomal dominant, nonsyndromic, progressive sensorineural hearing loss in a Chinese family. Using whole exome sequencing, we identified a missense variant (c.130C>T, p.R44C) in the MCM2 gene, which has a pro-apoptosis effect and is involved in the initiation of eukaryotic genome replication. This missense variant is very likely to be the disease causing variant. It segregated with hearing loss in this pedigree, and was not found in the dbSNP database or databases of genomes and SNP in the Chinese population, in 76 patients with sporadic hearing loss, or in 145 normal individuals. We performed western blot and immunofluorescence to test the MCM2 protein expression in the cochlea of rats and guinea pigs, demonstrating that MCM2 was widely expressed in the cochlea and was also surprisingly expressed in the cytoplasm of terminally differentiated hair cells. We then transiently expressed the variant MCM2 cDNA in HEK293 cells, and found that these cells displayed a slight increase in apoptosis without any changes in proliferation or cell cycle, supporting the view that this variant is pathogenic. In summary, we have identified MCM2 as a novel gene responsible for nonsyndromic hearing loss of autosomal dominant inheritance in a Chinese family.
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Peking University First Hospital, Beijing, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Peking University First Hospital, Beijing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Peking University First Hospital, Beijing, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Dong
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Peking University First Hospital, Beijing, China.
authors.forename: Siqi
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of central laboratory, Peking University First Hospital, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Peking University First Hospital, Beijing, China.
authors.forename: Yuhe
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D059472:Exome; D005260:Female; D006168:Guinea Pigs; D057809:HEK293 Cells; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2 / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2