Is LMNB1 a susceptibility gene for neural tube defects in humans?

Alexis Robinson; Darren Partridge; Ashraf Malhas; Sandra C.P Castro; Peter Gustavsson; Dominic N Thompson; David J Vaux; Andrew J Copp; Philip Stanier; Alexander G Bassuk; Nicholas D.E Greene

doi:10.1002/bdra.23141

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Is LMNB1 a susceptibility gene for neural tube defects in humans?

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Is LMNB1 a susceptibility gene for neural tube defects in humans?

Alexis Robinson, Darren Partridge, Ashraf Malhas, Sandra C.P Castro, Peter Gustavsson, Dominic N Thompson, David J Vaux, Andrew J Copp, Philip Stanier, Alexander G Bassuk, …

Birth defects research. A Clinical and molecular teratology, Vol.97(6), pp.398-402

06/2013

DOI: 10.1002/bdra.23141

PMCID: PMC3738925

PMID: 23733478

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Abstract

BACKGROUND Lamins are intermediate filament proteins that form a major component of the nuclear lamina, a protein complex at the surface of the inner nuclear membrane. Numerous clinically diverse conditions, termed laminopathies, have been found to result from mutation of LMNA. In contrast, coding or loss of function mutations of LMNB1, encoding lamin B1, have not been identified in human disease. In mice, polymorphism in Lmnb1 has been shown to modify risk of neural tube defects (NTDs), malformations of the central nervous system that result from incomplete closure of the neural folds. METHODS Mutation analysis by DNA sequencing was performed on all exons of LMNB1 in 239 samples from patients with NTDs from the United Kingdom, Sweden, and United States. Possible functional effects of missense variants were analyzed by bioinformatics prediction and fluorescence in photobleaching. RESULTS In NTD patients, we identified two unique missense variants that were predicted to disrupt protein structure/function and represent putative contributory mutations. Fluorescence loss in photobleaching analysis showed that the A436T variant compromised stability of lamin B1 interaction within the lamina. CONCLUSION The genetic basis of human NTDs appears highly heterogenous with possible involvement of multiple predisposing genes. We hypothesize that rare variants of LMNB1 may contribute to susceptibility to NTDs. Birth Defects Research (Part A) 97:398–402, 2013. © 2013 Wiley Periodicals, Inc.

nuclear lamina

anencephaly

neural tube defects

spina bifida

lamin B1

Details

Title: Subtitle: Is LMNB1 a susceptibility gene for neural tube defects in humans?
Creators: Alexis Robinson - Institute of Child Health
Darren Partridge - Institute of Child Health
Ashraf Malhas - University of Oxford
Sandra C.P Castro - Institute of Child Health
Peter Gustavsson - Karolinska Institutet
Dominic N Thompson - Great Ormond Street Hospital for Children NHS Trust
David J Vaux - University of Oxford
Andrew J Copp - Institute of Child Health
Philip Stanier - Institute of Child Health
Alexander G Bassuk - University of Iowa
Nicholas D.E Greene - Institute of Child Health
Resource Type: Journal article
Publication Details: Birth defects research. A Clinical and molecular teratology, Vol.97(6), pp.398-402
DOI: 10.1002/bdra.23141
PMID: 23733478
PMCID: PMC3738925
NLM abbreviation: Birth Defects Res A Clin Mol Teratol
ISSN: 1542-0752
eISSN: 1542-0760
Publisher: Wiley
Number of pages: 5
Grant note: Darren Partridge's current address is: Department of Medicine, Monash University Central Clinical School, Prahran, Victoria 3181, Australia
Language: English
Date published: 06/2013
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
Record Identifier: 9984020748902771

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