Del Campo M, Jones M C, Veraksa A N, Curry C J, Jones K L, Mascarello J T, Ali-Kahn-Catts Z, Drumheller T, McGinnis W
Division of Dysmorphology, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
Am J Hum Genet. 1999 Jul;65(1):104-10. doi: 10.1086/302467.
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.
脊椎动物有四组Hox基因（HoxA、HoxB、HoxC和HoxD）。各种表达和突变研究表明，HoxA和HoxD基因簇的后部成员在脊椎动物肢体发育中起重要作用。在人类中，HOXD13突变与II型并指或并指多指畸形相关，而HOXA13突变与手足生殖器综合征相关。我们研究了两名不相关的儿童，他们在前-后（a-p）肢体轴和生殖器上有以前未报道的严重发育缺陷模式，包括zeugopod中的单一骨骼、所有四肢自手（足）部的单指畸形或多指畸形，以及阴茎阴囊发育不全。两名儿童均为杂合子，存在一种缺失，该缺失消除了HOXD基因簇中的九个基因中的至少八个（HOXD3-HOXD13）。我们认为患者的表型部分归因于HOXD基因簇基因的单倍剂量不足。这一假设得到了这些基因在早期脊椎动物胚胎中的表达模式的支持。然而，该区域其他基因的参与可以解释这些人类表型与HoxD基因簇半合子小鼠中存在的较轻、非极化表型之间在严重程度上的不一致。这些病例代表了脊椎动物中首次报道的整个Hox基因簇缺陷的例子，并表明人类HOXD基因的二倍体剂量对于四肢沿前后轴的正常生长和模式形成至关重要。
