Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2

TY - JOUR

T1 - Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2

AU - Dathe, Katarina

AU - Kjaer, Klaus W

AU - Brehm, Anja

AU - Meinecke, Peter

AU - Nürnberg, Peter

AU - Neto, Jordao C

AU - Brunoni, Decio

AU - Tommerup, Niels

AU - Ott, Claus E

AU - Klopocki, Eva

AU - Seemann, Petra

AU - Mundlos, Stefan

N1 - Keywords: Adult; Animals; Base Sequence; Bone Morphogenetic Protein 2; Chromosomes, Human, Pair 20; Comparative Genomic Hybridization; Conserved Sequence; DNA; DNA Primers; Female; Fingers; Gene Duplication; Gene Expression Regulation, Developmental; Humans; Infant; Limb Deformities, Congenital; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pedigree; Phenotype; Regulatory Elements, Transcriptional; Tandem Repeat Sequences

PY - 2009

Y1 - 2009

N2 - Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers, has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5). A linkage analysis performed in a mutation-negative family identified a novel locus for BDA2 on chromosome 20p12.3 that incorporates the gene for Bone morphogenetic protein 2 (BMP2). No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval of approximately 1.3 Mb was performed. A microduplication of approximately 5.5 kb in a noncoding sequence approximately 110 kb downstream of BMP2 was detected. Screening of other patients by qPCR revealed a similar duplication in a second family. The duplicated region contains evolutionary highly conserved sequences suggestive of a long-range regulator. By using a transgenic mouse model we can show that this sequence is able to drive expression of a X-Gal reporter construct in the limbs. The almost complete overlap with endogenous Bmp2 expression indicates that a limb-specific enhancer of Bmp2 is located within the identified duplication. Our results reveal an additional functional mechanism for the pathogenesis of BDA2, which is duplication of a regulatory element that affects the expression of BMP2 in the developing limb.

AB - Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers, has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5). A linkage analysis performed in a mutation-negative family identified a novel locus for BDA2 on chromosome 20p12.3 that incorporates the gene for Bone morphogenetic protein 2 (BMP2). No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval of approximately 1.3 Mb was performed. A microduplication of approximately 5.5 kb in a noncoding sequence approximately 110 kb downstream of BMP2 was detected. Screening of other patients by qPCR revealed a similar duplication in a second family. The duplicated region contains evolutionary highly conserved sequences suggestive of a long-range regulator. By using a transgenic mouse model we can show that this sequence is able to drive expression of a X-Gal reporter construct in the limbs. The almost complete overlap with endogenous Bmp2 expression indicates that a limb-specific enhancer of Bmp2 is located within the identified duplication. Our results reveal an additional functional mechanism for the pathogenesis of BDA2, which is duplication of a regulatory element that affects the expression of BMP2 in the developing limb.

U2 - 10.1016/j.ajhg.2009.03.001

DO - 10.1016/j.ajhg.2009.03.001

M3 - Journal article

C2 - 19327734

SN - 0002-9297

VL - 84

SP - 483

EP - 492

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -