Pseudodominant inheritance of Langer mesomelic dysplasia caused by a SHOX homeobox missense mutation.
We report the clinical and molecular analysis in a consanguineous family in which the skeletal dysplasias Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD) both segregate. A newborn male and his mother, both with Langer mesomelic dysplasia, are described. A homozygous SHOX homeobox point mutation, C517T, was identified by direct sequencing in the proband and his mother. The same mutation was present in the heterozygous state in the proband's father and in the maternal grandmother, both of whom had features of LWD. This C to T transition is predicted to cause an arginine to cysteine amino acid change in a highly conserved region of the recognition helix of the homeodomain, which may reduce the stability of the interaction between the SHOX protein and its target DNA. In addition, the mutation may disrupt a nuclear localization signal in SHOX. This is the first SHOX point mutation identified in a case of LMD, and the first case in which parent to child transmission of LMD has been described.
Department of Clinical and Molecular Genetics, Institute of Child Health, London, UK. dshears@ich.ucl.ac.uk
Deborah J
DJ
Shears
Encarna
E
Guillen-Navarro
Manuel
M
Sempere-Miralles
Rosario
R
Domingo-Jimenez
Peter J
PJ
Scambler
Robin M
RM
Winter
D001483:Base Sequence; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D017354:Point Mutation; D000074122:Short Stature Homeobox Protein
D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D004247:DNA