Document Detail

DLL3 as a candidate gene for vertebral malformations.
MedLine Citation:
PMID:  17041936     Owner:  NLM     Status:  MEDLINE    
Investigations have not identified a major locus for congenital vertebral malformations. Based on observations in mice, we hypothesized that mutations in DLL3, a member of the notch-signaling pathway, might contribute to human vertebral malformations. We sequenced the DLL3 gene in 50 patients with congenital vertebral malformations. A Caucasian male patient with VACTERL manifestations including a T5-T6 block vertebrae was heterozygous for a "G" to "A" missense mutation changing glycine to arginine at codon 269. This residue is conserved in mammals, including chimpanzee, mouse, dog, and rat. Additional testing in the patient did not show evidence of chromosome abnormalities. The patient's asymptomatic mother was also heterozygous for the missense mutation. Since this mutation was not observed in a control population and leads to an amino acid change, it may be clinically significant. The mutation was not found in a control population of 87 anonymous individuals. Several established mechanisms could explain the mutation in both the patient and his asymptomatic mother (susceptibility allele requiring additional environmental factors, somatic mosaicism, multigenic inheritance). Documenting the absence of the mutation in a larger control population or the presence of the mutation in additional affected patients, or documenting a functional difference in DLL3 would provide further evidence supporting its causal role.
Philip F Giampietro; Cathleen L Raggio; Cory Reynolds; Nader Ghebranious; James K Burmester; Ingrid Glurich; Kristen Rasmussen; Elizabeth McPherson; Richard M Pauli; Sanjay K Shukla; Sajid Merchant; F Stig Jacobsen; Thomas Faciszewski; Robert D Blank
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of medical genetics. Part A     Volume:  140     ISSN:  1552-4825     ISO Abbreviation:  Am. J. Med. Genet. A     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-11-01     Completed Date:  2007-01-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101235741     Medline TA:  Am J Med Genet A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2447-53     Citation Subset:  IM    
Copyright Information:
(c) 2006 Wiley-Liss, Inc.
Department of Medical Genetic Services, Marshfield Clinic, Marshfield, Wisconsin 54449, USA.
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MeSH Terms
Amino Acid Substitution
Base Sequence
Case-Control Studies
DNA Primers / genetics
Gene Frequency
Intracellular Signaling Peptides and Proteins / genetics*
Membrane Proteins / genetics*
Mutation, Missense
Scoliosis / congenital,  genetics
Signal Transduction
Spine / abnormalities*
Reg. No./Substance:
0/DLL3 protein, human; 0/DNA Primers; 0/Intracellular Signaling Peptides and Proteins; 0/Membrane Proteins

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