DLL3 as a candidate gene for vertebral malformations. Am J Med Genet A 2006 Nov 15;140(22):2447-53
Date
10/17/2006Pubmed ID
17041936DOI
10.1002/ajmg.a.31509Scopus ID
2-s2.0-33750590091 (requires institutional sign-in at Scopus site) 44 CitationsAbstract
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.
Author List
Giampietro PF, Raggio CL, Reynolds C, Ghebranious N, Burmester JK, Glurich I, Rasmussen K, McPherson E, Pauli RM, Shukla SK, Merchant S, Jacobsen FS, Faciszewski T, Blank RDMESH terms used to index this publication - Major topics in bold
AdultAlleles
Amino Acid Substitution
Animals
Base Sequence
Case-Control Studies
Child
DNA Primers
Female
Gene Frequency
Heterozygote
Humans
Intracellular Signaling Peptides and Proteins
Male
Membrane Proteins
Mutation, Missense
Scoliosis
Signal Transduction
Spine
