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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Homozygous Inactivating Mutations in the NKX3-2 Gene Result in Spondylo-Megaepiphyseal-Metaphyseal Dysplasia
American Journal of Human Genetics, Volume 85, No. 6, Year 2009
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Description
Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) is a rare skeletal dysplasia with only a few cases reported in the literature. Affected individuals have a disproportionate short stature with a short and stiff neck and trunk. The limbs appear relatively long and may show flexion contractures of the distal joints. The most remarkable radiographic features are the delayed and impaired ossification of the vertebral bodies as well as the presence of large epiphyseal ossification centers and wide growth plates in the long tubular bones. Numerous pseudoepiphyses of the short tubular bones in hands and feet are another remarkable feature of the disorder. Genome wide homozygosity mapping followed by a candidate gene approach resulted in the elucidation of the genetic cause in three new consanguineous families with SMMD. Each proband was homozygous for a different inactivating mutation in NKX3-2, a homeobox-containing gene located on chromosome 4p15.33. Striking similarities were found when comparing the vertebral ossification defects in SMMD patients with those observed in the Nkx3-2 null mice. Distinguishing features were the asplenia found in the mutant mice and the radiographic abnormalities in the limbs only observed in SMMD patients. The absence of the latter anomalies in the murine model may be due to the perinatal death of the affected animals. This study illustrates that NKX3-2 plays an important role in endochondral ossification of both the axial and appendicular skeleton in humans. In addition, it defines SMMD as yet another skeletal dysplasia with autosomal-recessive inheritance and a distinct phenotype. © 2009 The American Society of Human Genetics.
Authors & Co-Authors
Hellemans, Jan
Belgium, Ghent
Universitair Ziekenhuis Gent
Simon, Marleen E.H.
Netherlands, Rotterdam
Erasmus Mc
Dheedene, Annelies
Belgium, Ghent
Universitair Ziekenhuis Gent
Alanay, Yasemin
Turkey, Ankara
Hacettepe Üniversitesi
Mıhçı, Ercan
Turkey, Antalya
Akdeniz Üniversitesi
Rifai, Laïla
United States, Bethesda
National Institutes of Health Nih
Sefiani, Abdelaziz
United States, Bethesda
National Institutes of Health Nih
van Bever, Yolande
Netherlands, Rotterdam
Erasmus Mc
Superti-Furga, Andrea
Germany, Freiburg Im Breisgau
Universität Freiburg
Mortier, Geert R.
Belgium, Ghent
Universitair Ziekenhuis Gent
Statistics
Citations: 24
Authors: 10
Affiliations: 6
Identifiers
Doi:
10.1016/j.ajhg.2009.11.005
ISSN:
00029297
Research Areas
Cancer
Genetics And Genomics