title: DLL3 as a candidate gene for vertebral malformations.
abstract: 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.
authors.affiliation: Department of Medical Genetic Services, Marshfield Clinic, Marshfield, Wisconsin 54449, USA. giampietro.philip@marshfieldclinic.org
authors.forename: Philip F
authors.initials: PF
authors.lastname: Giampietro
authors.forename: Cathleen L
authors.initials: CL
authors.lastname: Raggio
authors.forename: Cory
authors.initials: C
authors.lastname: Reynolds
authors.forename: Nader
authors.initials: N
authors.lastname: Ghebranious
authors.forename: James K
authors.initials: JK
authors.lastname: Burmester
authors.forename: Ingrid
authors.initials: I
authors.lastname: Glurich
authors.forename: Kristen
authors.initials: K
authors.lastname: Rasmussen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McPherson
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pauli
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Shukla
authors.forename: Sajid
authors.initials: S
authors.lastname: Merchant
authors.forename: F Stig
authors.initials: FS
authors.lastname: Jacobsen
authors.forename: Thomas
authors.initials: T
authors.lastname: Faciszewski
authors.forename: Robert D
authors.initials: RD
authors.lastname: Blank
mesh_terms: D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020125:Mutation, Missense; D012600:Scoliosis / Q000151:congenital / Q000235:genetics; D015398:Signal Transduction; D013131:Spine / Q000002:abnormalities*
chemical_list: C496666:DLL3 protein, human; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins