Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy
Pia Ostergaard1, Michael A Simpson, Antonella Mendola
1Medical Genetics Unit, Biomedical Sciences, St. George's University of London, UK.
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.
Insights
Mutations in the KIF11 gene cause autosomal-dominant microcephaly, lymphedema, and chorioretinopathy. These findings highlight KIF11
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Ophthalmology and Neurology
Background:
- Syndromic microcephaly is a rare condition characterized by a smaller head circumference and associated developmental abnormalities.
- Lymphedema and chorioretinopathy are conditions affecting the lymphatic system and the retina, respectively, which can occur in complex genetic syndromes.
- The KIF11 gene encodes the Eg5 motor protein, crucial for cell division and spindle formation during mitosis.
Purpose of the Study:
- To investigate the genetic basis of syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy.
- To identify specific gene mutations responsible for this complex phenotype.
- To understand the role of the identified gene in central nervous system, retinal, and lymphatic development.
Main Methods:
- Whole-exome sequencing was performed on individuals with microcephaly and lymphedema.
- Sanger sequencing was used to validate and further screen for KIF11 mutations in additional patients.
- Analysis of mutation types (nonsense, splice site, missense, indels) and their predicted impact on KIF11 protein function.
Main Results:
- Heterozygous KIF11 mutations were identified in individuals with syndromic microcephaly, lymphedema, and/or chorioretinopathy.
- A significant proportion of unrelated microcephalic probands with lymphedema and/or chorioretinopathy carried KIF11 mutations.
- The identified mutations are predicted to impair the function of the KIF11-encoded Eg5 motor protein.
Conclusions:
- KIF11 mutations are a cause of syndromic autosomal-dominant microcephaly associated with lymphedema and chorioretinopathy.
- These findings underscore the critical role of spindle formation proteins, like Eg5, in central nervous system development.
- Eg5 is implicated in the development and maintenance of retinal and lymphatic structures, suggesting a broader role in tissue development.
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