title: Is LMNB1 a susceptibility gene for neural tube defects in humans?
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neural Development Unit and Newlife Birth Defects Research Centre, Institute of Child Health, University College London, United Kingdom.
authors.forename: Alexis
authors.initials: A
authors.lastname: Robinson
authors.forename: Darren
authors.initials: D
authors.lastname: Partridge
authors.forename: Ashraf
authors.initials: A
authors.lastname: Malhas
authors.forename: Sandra C P
authors.initials: SC
authors.lastname: De Castro
authors.forename: Peter
authors.initials: P
authors.lastname: Gustavsson
authors.forename: Dominic N
authors.initials: DN
authors.lastname: Thompson
authors.forename: David J
authors.initials: DJ
authors.lastname: Vaux
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Copp
authors.forename: Philip
authors.initials: P
authors.lastname: Stanier
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bassuk
authors.forename: Nicholas D E
authors.initials: ND
authors.lastname: Greene
mesh_terms: D015331:Cohort Studies; D019295:Computational Biology; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005453:Fluorescence; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D034921:Lamin Type B / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics; D009436:Neural Tube Defects / Q000235:genetics*; D034881:Nuclear Lamina / Q000378:metabolism; D038761:Photobleaching; D013548:Sweden; D006113:United Kingdom; D014481:United States
chemical_list: D034921:Lamin Type B