title: Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy.
abstract: We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures.
authors.affiliation: Medical Genetics Unit, Biomedical Sciences, St. George's University of London, UK.
authors.forename: Pia
authors.initials: P
authors.lastname: Ostergaard
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Antonella
authors.initials: A
authors.lastname: Mendola
authors.forename: Pradeep
authors.initials: P
authors.lastname: Vasudevan
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Connell
authors.forename: Andreas
authors.initials: A
authors.lastname: van Impel
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: Bart L
authors.initials: BL
authors.lastname: Loeys
authors.forename: Arash
authors.initials: A
authors.lastname: Ghalamkarpour
authors.forename: Alexandros
authors.initials: A
authors.lastname: Onoufriadis
authors.forename: Ines
authors.initials: I
authors.lastname: Martinez-Corral
authors.forename: Sophie
authors.initials: S
authors.lastname: Devery
authors.forename: Jules G
authors.initials: JG
authors.lastname: Leroy
authors.forename: Lut
authors.initials: L
authors.lastname: van Laer
authors.forename: Amihood
authors.initials: A
authors.lastname: Singer
authors.forename: Martin G
authors.initials: MG
authors.lastname: Bialer
authors.forename: Meriel
authors.initials: M
authors.lastname: McEntagart
authors.forename: Oliver
authors.initials: O
authors.lastname: Quarrell
authors.forename: Glen
authors.initials: G
authors.lastname: Brice
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulte-Merker
authors.forename: Taija
authors.initials: T
authors.lastname: Makinen
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
authors.forename: Peter S
authors.initials: PS
authors.lastname: Mortimer
authors.forename: Sahar
authors.initials: S
authors.lastname: Mansour
authors.forename: Steve
authors.initials: S
authors.lastname: Jeffery
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D002779:Cholestasis / Q000235:genetics*; D015331:Cohort Studies; D000013:Congenital Abnormalities / Q000235:genetics*; D059472:Exome; D019066:Facies; D005260:Female; D006579:Heterozygote; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008209:Lymphedema / Q000151:congenital* / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D015792:Retinal Dysplasia / Q000235:genetics
chemical_list: C470243:KIF11 protein, human; D016547:Kinesins