HOXD13, the most 5' gene of the HOXD cluster, encodes a homeodomain transcription factor with important functions in limb patterning and growth. Heterozygous mutations of human HOXD13, encoding polyalanine expansions or frameshifts, are believed to act by dominant negative or haploinsufficiency mechanisms and are predominantly associated with synpolydactyly phenotypes. Here, we describe two mutations of HOXD13 (923C-->G encoding Ser308Cys and 940A-->C encoding Ile314Leu) that cause missense substitutions within the homeodomain. Both are associated with distinctive limb phenotypes in which brachydactyly of specific metacarpals, metatarsals, and phalangeal bones is the most constant feature, exhibiting overlap with brachydactyly types D and E. We investigated the binding of synthetic mutant proteins to double-stranded DNA targets in vitro. No consistent differences were found for the Ser308Cys mutation compared with the wild type, but the Ile314Leu mutation (which resides at the 47th position of the homeodomain) exhibited increased affinity for a target containing the core recognition sequence 5'-TTAC-3' but decreased affinity for a 5'-TTAT-3' target. Molecular modeling of the Ile314Leu mutation indicates that this mixed gain and loss of affinity may be accounted for by the relative positions of methyl groups in the amino acid side chain and target base.

中文翻译：

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HOXD13 同源域的错义突变与 D 型和 E 型短指相关。


HOXD13 是 HOXD 簇最 5' 端的基因，编码同源域转录因子，在肢体模式和生长中具有重要功能。编码多聚丙氨酸扩展或移码的人类 HOXD13 杂合突变被认为通过显性失活或单倍体不足机制起作用，并且主要与并多指表型相关。在这里，我们描述了 HOXD13 的两个突变（编码 Ser308Cys 的 923C-->G 和编码 Ile314Leu 的 940A-->C），它们导致同源域内的错义替换。两者都与独特的肢体表型相关，其中特定掌骨、跖骨和指骨的短指是最恒定的特征，与 D 型和 E 型短指有重叠。我们在体外研究了合成突变蛋白与双链 DNA 靶标的结合。与野生型相比，Ser308Cys 突变没有发现一致的差异，但 Ile314Leu 突变（位于同源域的第 47 位）对包含核心识别序列 5'-TTAC-3' 的靶点表现出增加的亲和力，但降低对 5'-TTAT-3' 靶标的亲和力。 Ile314Leu 突变的分子模型表明，这种亲和力的增加和损失混合可能是由氨基酸侧链和靶碱基中甲基的相对位置造成的。