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: Pia Ostergaard, Michael A Simpson, Antonella Mendola, Pradeep Vasudevan, Fiona C Connell, Andreas van Impel, Anthony T Moore, Bart L Loeys, Arash Ghalamkarpour, Alexandros Onoufriadis, Ines Martinez-Corral, Sophie Devery, Jules G Leroy, Lut van Laer, Amihood Singer, Martin G Bialer, Meriel McEntagart, Oliver Quarrell, Glen Brice, Richard C Trembath, Stefan Schulte-Merker, Taija Makinen, Miikka Vikkula, Peter S Mortimer, Sahar Mansour, Steve Jeffery
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 90 Issue 2 Pg. 356-62 (Feb 10 2012) ISSN: 1537-6605 [Electronic] United States
• PMID: 22284827 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• KIF11 protein, human
• Kinesins

Topics

• Abnormalities, Multiple (genetics)
• Cholestasis (genetics)
• Cohort Studies
• Congenital Abnormalities (genetics)
• Exome
• Facies
• Female
• Heterozygote
• Humans
• Kinesins (genetics)
• Lymphedema (congenital, genetics)
• Male
• Microcephaly (genetics)
• Mutation
• Pedigree
• Phenotype
• Retinal Dysplasia (genetics)