A genomic rearrangement resulting in a tandem duplication is associated with split hand-split foot malformation 3 (SHFM3) at 10q24.
Split hand-split foot malformation (SHFM) is characterized by hypoplasia/aplasia of the central digits with fusion of the remaining digits. SHFM is usually an autosomal dominant condition and at least five loci have been identified in humans. Mutation analysis of the DACTYLIN gene, suspected to be responsible for SHFM3 in chromosome 10q24, was conducted in seven SHFM patients. We screened the coding region of DACTYLIN by single-strand conformation polymorphism and sequencing, and found no point mutations. However, Southern, pulsed field gel electrophoresis and dosage analyses demonstrated a complex rearrangement associated with a approximately 0.5 Mb tandem duplication in all the patients. The distal and proximal breakpoints were within an 80 and 130 kb region, respectively. This duplicated region contained a disrupted extra copy of the DACTYLIN gene and the entire LBX1 and beta-TRCP genes, known to be involved in limb development. The possible role of these genes in the SHFM3 phenotype is discussed.
de Mollerat
Xavier J
XJ
Center for Molecular Studies, J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC, USA.
Gurrieri
Fiorella
F
Morgan
Chad T
CT
Sangiorgi
Eugenio
E
Everman
David B
DB
Gaspari
Paola
P
Amiel
Jeanne
J
Bamshad
Michael J
MJ
Lyle
Robert
R
Blouin
Jean-Louis
JL
Allanson
Judith E
JE
Le Marec
Bernard
B
Wilson
Melba
M
Braverman
Nancy E
NE
Radhakrishna
Uppala
U
Delozier-Blanchet
Celia
C
Abbott
Albert
A
Elghouzzi
Vincent
V
Antonarakis
Stylianos
S
Stevenson
Roger E
RE
Munnich
Arnold
A
Neri
Giovanni
G
Schwartz
Charles E
CE
D000015:Abnormalities, Multiple / Q000235:genetics*; D002461:Cell Line, Transformed; D002869:Chromosome Aberrations; D002879:Chromosomes, Human, Pair 10; D016521:Electrophoresis, Gel, Pulsed-Field; D044783:F-Box Proteins; D005530:Foot Deformities / Q000235:genetics*; D020440:Gene Duplication; D006226:Hand Deformities / Q000235:genetics*; D006801:Humans; D006822:Hybrid Cells; D008957:Models, Genetic; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA
D044783:F-Box Proteins; C120449:FBXW4 protein, human; D011506:Proteins