Akarsu A N, Stoilov I, Yilmaz E, Sayli B S, Sarfarazi M
Department of Surgery, University of Connecticut Health Center, Farmington, USA.
Hum Mol Genet. 1996 Jul;5(7):945-52. doi: 10.1093/hmg/5.7.945.
Synpolydactyly (SPD) is a limb malformation that shows a characteristic manifestation in both hands and feet. This condition is inherited as an autosomal dominant trait with reduced penetrance. We have recently mapped this locus centromeric to the HOXD8 intragenic marker and suggested the HOXD13 gene as a potential candidate for this condition. The genomic structure of HOXD13 established in this study consists of two exons that encodes a polypeptide of 335 amino acids. The downstream exon at the 3' end of this gene contains the homeodomain sequences that are highly conserved. Sixty-three bp upstream of this exon lies a stretch of intronic CA-repeats that proved to be polymorphic in two different populations. The upstream exon encodes 75% of the entire protein and contains a stretch of 15 normal alanines at its 5' end. Sequence comparison at this position in the homozygous affected individuals identified a total of 24 alanine residues that resulted from a duplication of nine polyalanines. In two unrelated SPD families, this duplication was directly transmitted from the affected parents to their affected, but not unaffected, offspring; in one family its size has remained constant for at least 150 years spanning over seven generations. The presence of this duplication confirmed the status of four normal gene carriers, one incomplete penetrance and two affected individuals who were recombinants for HOXD8 or HOXD13-CA repeat markers. This duplication was not present in 150 chromosomes of unrelated healthy subjects of two different populations.
多指（趾）并指（趾）畸形（SPD）是一种肢体畸形，在手和脚上均有特征性表现。这种疾病以常染色体显性性状遗传，外显率降低。我们最近将该基因座定位于HOXD8基因内标记的着丝粒区域，并提出HOXD13基因可能是导致这种疾病的候选基因。本研究确定的HOXD13基因的基因组结构由两个外显子组成，编码一个含335个氨基酸的多肽。该基因3'端的下游外显子包含高度保守的同源结构域序列。在该外显子上游63 bp处有一段内含子CA重复序列，在两个不同人群中被证明具有多态性。上游外显子编码整个蛋白质的75%，在其5'端含有一段15个正常丙氨酸的序列。对纯合受累个体该位置的序列比较发现，共有24个丙氨酸残基是由9个多丙氨酸重复产生的。在两个不相关的SPD家族中，这种重复直接从受累父母遗传给他们受累而非未受累的后代；在一个家族中，其大小在跨越七代的至少150年里一直保持不变。这种重复的存在证实了4名正常基因携带者、1名不完全外显者以及2名HOXD8或HOXD13 - CA重复标记重组的受累个体的情况。在两个不同人群的150名不相关健康受试者的染色体中未发现这种重复。
