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Pycnodysostosis (MIM 265800) is a rare, autosomal recessive skeletal dysplasia characterized by short stature, wide cranial sutures, and increased bone density and fragility. Linkage analysis localized the disease gene to human chromosome 1q21, and subsequently the genetic interval was narrowed to between markers D1S2612 and D1S2345. Expressed sequence tagged markers corresponding to cathepsin K, a cysteine protease highly expressed in osteoclasts and thought to be important in bone resorption, were mapped previously in the candidate region. We have identified a cytosine to thymidine transition at nucleotide 862 (GenBank accession no. S79895) of the cathepsin K coding sequence in the DNA of an affected individual from a large, consanguinous Mexican family. This mutation results in an arginine to STOP alteration at amino acid 241, predicting premature termination of cathepsin K mRNA translation. All affected individuals in this family were homozygous for the mutation, suggesting that this alteration may lead to pycnodysostosis. Recognition of the role of cathepsin K in the etiology of pycnodysostosis should provide insights into the pathogenesis and treatment of other disorders of bone remodeling, including osteoporosis.

Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by disproportionate dwarfism, polydactyly, and congenital heart disease. This rare disorder is found with increased frequency among the Old Order Amish community in Lancaster County, Pennsylvania. We have used linkage analysis to localize the gene responsible for the EVC phenotype in nine interrelated Amish pedigrees and three unrelated families from Mexico, Ecuador, and Brazil. We now report the linkage for the Ellis-van Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Zmax = 6.91 at theta = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype.