Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping

Pycnodysostosis is an autosomal recessive sclerosing skeletal dysplasia of unknown aetiology which is inherited with complete penetrance. The clinical features, fully delineated in 1962 by Maroteaux & Lamy and by Andrén et al., include osteosclerosis, acro-osteolysis of the distal phalanges, bone fragility, clavicular dysplasia, reduced stature and skull deformities with delayed suture closure. Although rare, pycnodysostosis has attained prominence because the French artist Henri de Toulouse-Lautrec was retrospectively diagnosed as having been affected with this disorder. For rare autosomal recessive traits, homozygosity mapping provides a powerful approach to disease gene mapping. We have now used this approach to map the locus for pycnodysostosis. Following a genome-wide search in a large Arab family with 16 affected relatives, we established linkage to a narrow region on chromosome 1q21, with a maximal lod score of 11.72. A single marker, D1S498, was homozygous-by-descent in all affecteds and defined the gene locus to a region of 4 cM. Two candidate genes in the region--the interleukin-6 receptor gene (IL6R) and the myeloid cell leukaemia-1 gene (MCL1)--are involved in the differentiation of monocyte/macrophages into osteoclasts, the most likely site of the primary defect in pycnodysostosis.