Breakpoints around the HOXD cluster result in various limb malformations.
BACKGROUND
Characterisation of disease associated balanced chromosome rearrangements is a promising starting point in the search for candidate genes and regulatory elements.


METHODS
We have identified and investigated three patients with limb abnormalities and breakpoints involving chromosome 2q31. Patient 1 with severe brachydactyly and syndactyly, mental retardation, hypoplasia of the cerebellum, scoliosis, and ectopic anus, carries a balanced t(2;10)(q31.1;q26.3) translocation. Patient 2, with translocation t(2;10)(q31.1;q23.33), has aplasia of the ulna, shortening of the radius, finger anomalies, and scoliosis. Patient 3 carries a pericentric inversion of chromosome 2, inv(2)(p15q31). Her phenotype is characterised by bilateral aplasia of the fibula and the radius, bilateral hypoplasia of the ulna, unossified carpal bones, and hypoplasia and dislocation of both tibiae.


RESULTS
By fluorescence in situ hybridisation, we have mapped the breakpoints to intervals of approximately 170 kb or less. None of the three 2q31 breakpoints, which all mapped close to the HOXD cluster, disrupted any known genes.


CONCLUSIONS
Hoxd gene expression in the mouse is regulated by cis-acting DNA elements acting over distances of several hundred kilobases. Moreover, Hoxd genes play an established role in bone development. It is therefore very likely that the three rearrangements disturb normal HOXD gene regulation by position effects.
Dlugaszewska
B
B
Max Planck Institute for Molecular Genetics, Ihnestrasse 73, D-14195 Berlin, Germany.
Silahtaroglu
A
A
Menzel
C
C
Kübart
S
S
Cohen
M
M
Mundlos
S
S
Tümer
Z
Z
Kjaer
K
K
Friedrich
U
U
Ropers
H-H
HH
Tommerup
N
N
Neitzel
H
H
Kalscheuer
V M
VM
D000293:Adolescent; D000328:Adult; D019457:Chromosome Breakage / Q000235:genetics*; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D019295:Computational Biology; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007231:Infant, Newborn; D007621:Karyotyping; D017880:Limb Deformities, Congenital / Q000235:genetics*; D008297:Male; D005810:Multigene Family / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
C513184:HOXD13 protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors