Vanhorne J B, Gimm O, Myers S M, Kaushik A, von Deimling A, Eng C, Mulligan L M
Department of Pathology, Queen's University, Kingston, Ontario, Canada.
Hum Genet. 2001 May;108(5):409-15. doi: 10.1007/s004390100506.
The glial-cell-line-derived neurotrophic factor (GDNF) family receptors alpha (GFRalpha) are cell surface bound glycoproteins that mediate interactions of the GDNF ligand family with the RET receptor. These interactions are crucial to the development of the kidney and some peripheral nerve lineages. In humans, mutations of RET or RET ligands are associated with the congenital abnormality Hirschsprung disease (HSCR) in which nerves and ganglia of the hind gut are absent. As the GFRalpha family are required for normal activation of the RET receptor, they are also candidates for a role in HSCR. The GFRA2 gene, which is required for the development of the myenteric nerve plexus, is an excellent candidate gene for HSCR. In this study, we cloned the human GFRA2 locus, characterized the gene structure, and compared it with other GFRA family members. We further investigated the GFRA2 gene for mutations in a panel of HSCR patients. GFRA2 has nine coding exons that are similar in size and organization to those of other GFRA family genes. We identified six sequence variants of GFRA2, four of which did not affect the amino acid sequence of the GFRalpha-2 protein. Two further changes that resulted in amino acid substitutions were found in exon 9 and were predicted to lie in the amino acid sequence encoding the glycosylphosphatidylinositol-linkage signal of GFRalpha-2. There was no difference in frequency of any of the sequence variants between control and HSCR populations. Our data indicate that members of the GFRA gene family are closely related in intron/exon structure and in sequence. We have not detected any correlation between sequence variants of GFRA2 and the HSCR phenotype.
胶质细胞系源性神经营养因子（GDNF）家族受体α（GFRα）是细胞表面结合糖蛋白，介导GDNF配体家族与RET受体的相互作用。这些相互作用对肾脏和一些周围神经谱系的发育至关重要。在人类中，RET或RET配体的突变与先天性异常先天性巨结肠病（HSCR）相关，其中后肠的神经和神经节缺失。由于GFRα家族是RET受体正常激活所必需的，它们也是HSCR发病机制中的候选因素。肌间神经丛发育所必需的GFRA2基因是HSCR的一个优秀候选基因。在本研究中，我们克隆了人类GFRA2基因座，表征了基因结构，并将其与其他GFRA家族成员进行了比较。我们进一步研究了一组HSCR患者中GFRA2基因的突变情况。GFRA2有9个编码外显子，其大小和组织与其他GFRA家族基因相似。我们鉴定出GFRA2的6个序列变异体，其中4个不影响GFRα-2蛋白的氨基酸序列。在第9外显子中发现了另外两个导致氨基酸替换的变化，预计位于编码GFRα-2糖基磷脂酰肌醇连接信号的氨基酸序列中。对照人群和HSCR人群中任何序列变异体的频率均无差异。我们的数据表明，GFRA基因家族成员在内含子/外显子结构和序列上密切相关。我们未检测到GFRA2序列变异体与HSCR表型之间的任何相关性。
