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Am J Hum Genet. 2014 Jan 2;94(1):87-94. doi: 10.1016/j.ajhg.2013.10.001. Epub 2013 Nov 14.

Mutations in KPTN cause macrocephaly, neurodevelopmental delay, and seizures.

Author information

1
Monogenic Molecular Genetics, University of Exeter Medical School, St. Luke's Campus, Magdalen Road, Exeter EX1 2LU, UK.
2
Institute for Biochemistry I, Jena University Hospital and Friedrich Schiller University Jena, D-07743 Jena, Germany.
3
Department of Ophthalmology and Vision Science, University of Arizona School of Medicine, 655 N. Alvernon Way, Tucson, AZ 85711, USA.
4
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
5
Laboratory of Neuronal Plasticity & Behaviour, University of Exeter Medical School, Hatherly Laboratories, Prince of Wales Road, Exeter EX4 4PS, UK.
6
Windows of Hope Genetic Study, Holmes County, OH 44687, USA.
7
South West Thames Regional Genetics Service, St. George's Healthcare NHS Trust, London SW17 0QT, UK.
8
Department of Neuroradiology, St. George's Hospital, London SW17 0QT, UK.
9
Monogenic Molecular Genetics, University of Exeter Medical School, St. Luke's Campus, Magdalen Road, Exeter EX1 2LU, UK. Electronic address: a.h.crosby@exeter.ac.uk.

Abstract

The proper development of neuronal circuits during neuromorphogenesis and neuronal-network formation is critically dependent on a coordinated and intricate series of molecular and cellular cues and responses. Although the cortical actin cytoskeleton is known to play a key role in neuromorphogenesis, relatively little is known about the specific molecules important for this process. Using linkage analysis and whole-exome sequencing on samples from families from the Amish community of Ohio, we have demonstrated that mutations in KPTN, encoding kaptin, cause a syndrome typified by macrocephaly, neurodevelopmental delay, and seizures. Our immunofluorescence analyses in primary neuronal cell cultures showed that endogenous and GFP-tagged kaptin associates with dynamic actin cytoskeletal structures and that this association is lost upon introduction of the identified mutations. Taken together, our studies have identified kaptin alterations responsible for macrocephaly and neurodevelopmental delay and define kaptin as a molecule crucial for normal human neuromorphogenesis.

PMID:
24239382
PMCID:
PMC3882725
DOI:
10.1016/j.ajhg.2013.10.001
[Indexed for MEDLINE]
Free PMC Article
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