title: Mcph1-deficient mice reveal a role for MCPH1 in otitis media.
abstract: Otitis media is a common reason for hearing loss, especially in children. Otitis media is a multifactorial disease and environmental factors, anatomic dysmorphology and genetic predisposition can all contribute to its pathogenesis. However, the reasons for the variable susceptibility to otitis media are elusive. MCPH1 mutations cause primary microcephaly in humans. So far, no hearing impairment has been reported either in the MCPH1 patients or mouse models with Mcph1 deficiency. In this study, Mcph1-deficient (Mcph1(tm1a) (/tm1a) ) mice were produced using embryonic stem cells with a targeted mutation by the Sanger Institute's Mouse Genetics Project. Auditory brainstem response measurements revealed that Mcph1(tm1a) (/tm1a) mice had mild to moderate hearing impairment with around 70% penetrance. We found otitis media with effusion in the hearing-impaired Mcph1(tm1a) (/tm1a) mice by anatomic and histological examinations. Expression of Mcph1 in the epithelial cells of middle ear cavities supported its involvement in the development of otitis media. Other defects of Mcph1(tm1a) (/tm1a) mice included small skull sizes, increased micronuclei in red blood cells, increased B cells and ocular abnormalities. These findings not only recapitulated the defects found in other Mcph1-deficient mice or MCPH1 patients, but also revealed an unexpected phenotype, otitis media with hearing impairment, which suggests Mcph1 is a new gene underlying genetic predisposition to otitis media.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Neil
authors.initials: N
authors.lastname: Ingham
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.forename: Claire
authors.initials: C
authors.lastname: Raisen
authors.forename: Valerie E
authors.initials: VE
authors.lastname: Vancollie
authors.forename: Ozama
authors.initials: O
authors.lastname: Ismail
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: McIntyre
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Tsang
authors.forename: Vinit B
authors.initials: VB
authors.lastname: Mahajan
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: White
authors.forename: Karen P
authors.initials: KP
authors.lastname: Steel
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D007758:Ear, Inner / Q000473:pathology / Q000648:ultrastructure; D004432:Ear, Middle / Q000473:pathology; D005124:Eye Abnormalities / Q000235:genetics / Q000473:pathology; D015870:Gene Expression; D023061:Gene Order; D018390:Gene Targeting; D005822:Genetic Vectors / Q000235:genetics; D042822:Genomic Instability; D005838:Genotype; D034381:Hearing Loss / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010033:Otitis Media / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D012886:Skull / Q000473:pathology
chemical_list: D000907:Antibodies, Bacterial; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D003598:Cytoskeletal Proteins; C547654:MCPH1 protein, mouse