Copyright © 1999 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 65, Issue 1, 104-110, 1 July 1999
doi:10.1086/302467
Monodactylous Limbs and Abnormal Genitalia Are Associated with Hemizygosity for the Human 2q31 Region That Includes the HOXD Cluster
Miguel Del Campo1, Marilyn C. Jones3, Alexey N. Veraksa2, Cindy J. Curry4, Kenneth L. Jones1, James T. Mascarello3, Zohra Ali-Kahn-Catts4, Timothy Drumheller4 and William McGinnis2, 
, 
1 Division of Dysmorphology, Department of Pediatrics, San Diego, La Jolla
2 Department of Biology, University of California, San Diego, La Jolla
3 Division of Dysmorphology and Genetics, Children's Hospital, San Diego
4 Genetic Medicine, Valley Children's Hospital/UCSF, Madera, CA
Address for correspondence and reprints: Dr. William McGinnis, Department of Biology 0349, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0349Abstract
Vertebrates have four clusters of Hox genes (HoxA, HoxB, HoxC, and HoxD). A variety of expression and mutation studies indicate that posterior members of the HoxA and HoxD clusters play an important role in vertebrate limb development. In humans, mutations in HOXD13 have been associated with type II syndactyly or synpolydactyly, and, in HOXA13, with hand-foot-genital syndrome. We have investigated two unrelated children with a previously unreported pattern of severe developmental defects on the anterior-posterior (a-p) limb axis and in the genitalia, consisting of a single bone in the zeugopod, either monodactyly or oligodactyly in the autopod of all four limbs, and penoscrotal hypoplasia. Both children are heterozygous for a deletion that eliminates at least eight (HOXD3–HOXD13) of the nine genes in the HOXD cluster. We propose that the patients' phenotypes are due in part to haploinsufficiency for HOXD-cluster genes. This hypothesis is supported by the expression patterns of these genes in early vertebrate embryos. However, the involvement of additional genes in the region could explain the discordance, in severity, between these human phenotypes and the milder, non-polarized phenotypes present in mice hemizygous for HoxD cluster genes. These cases represent the first reported examples of deficiencies for an entire Hox cluster in vertebrates and suggest that the diploid dose of human HOXD genes is crucial for normal growth and patterning of the limbs along the anterior-posterior axis.
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