TY - JOUR
T1 - Breakpoints around the HOXD cluster result in various limb malformations
AU - Dlugaszewska, B
AU - Silahtaroglu, A
AU - Menzel, C
AU - Kübart, S
AU - Cohen, M
AU - Mundlos, S
AU - Tümer, Z
AU - Kjaer, K
AU - Friedrich, U
AU - Ropers, H-H
AU - Tommerup, N
AU - Neitzel, H
AU - Kalscheuer, V M
PY - 2006/2
Y1 - 2006/2
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Chromosome Breakage/genetics
KW - Chromosome Mapping
KW - Chromosomes, Human, Pair 2/genetics
KW - Computational Biology
KW - Female
KW - Homeodomain Proteins/genetics
KW - Humans
KW - In Situ Hybridization, Fluorescence
KW - Infant, Newborn
KW - Karyotyping
KW - Limb Deformities, Congenital/genetics
KW - Male
KW - Multigene Family/genetics
KW - Mutation/genetics
KW - Transcription Factors/genetics
U2 - 10.1136/jmg.2005.033555
DO - 10.1136/jmg.2005.033555
M3 - Journal article
C2 - 15980115
SN - 0022-2593
VL - 43
SP - 111
EP - 118
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 2
ER -