Angrist M, Jing S, Bolk S, Bentley K, Nallasamy S, Halushka M, Fox G M, Chakravarti A
Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106-4955, USA.
Genomics. 1998 Mar 15;48(3):354-62. doi: 10.1006/geno.1997.5191.
Congenital aganglionic megacolon, commonly known as Hirschsprung disease (HSCR), is the most frequent cause of congenital bowel obstruction. Germline mutations in the RET receptor tyrosine kinase have been shown to cause HSCR. Knockout mice for RET and for its ligand, glial cell line-derived neurotrophic factor (GDNF), exhibit both complete intestinal aganglionosis and renal defects. Recently, GDNF and GFRA1 (GDNF family receptor, also known as GDNFR-alpha), its GPI-linked coreceptor, were demonstrated to be components of a functional ligand for RET. Moreover, GDNF has been implicated in rare cases of HSCR. We have mapped GFRA1 to human chromosome 10q25, isolated human and mouse genomic clones, determined the gene's intron-exon boundaries, isolated a highly polymorphic microsatellite marker adjacent to exon 7, and scanned for GFRA1 mutations in a large panel of HSCR patients. No evidence of linkage was detected in HSCR kindreds, and no sequence variants were found to be in significant excess in patients. These data suggest that GFRA1'S role in enteric neurogenesis in humans remains to be elucidated and that RET signaling in the gut may take place via alternate pathways, such as the recently described GDNF-related molecule neurturin and its GFRA1-like coreceptor, GFRA2.
先天性无神经节巨结肠，通常称为先天性巨结肠症（HSCR），是先天性肠梗阻最常见的病因。研究表明，RET受体酪氨酸激酶的种系突变会导致先天性巨结肠症。RET基因敲除小鼠及其配体胶质细胞系源性神经营养因子（GDNF）基因敲除小鼠均表现出完全性肠无神经节症和肾脏缺陷。最近，GDNF及其糖基磷脂酰肌醇连接的共受体GFRA1（GDNF家族受体，也称为GDNFR-α）被证明是RET功能性配体的组成部分。此外，GDNF与罕见的先天性巨结肠症病例有关。我们已将GFRA1定位于人类染色体10q25，分离出人类和小鼠基因组克隆，确定了该基因的内含子-外显子边界，分离出一个与外显子7相邻的高度多态性微卫星标记，并在一大组先天性巨结肠症患者中筛查GFRA1突变。在先天性巨结肠症家族中未检测到连锁证据，在患者中也未发现序列变异显著增多。这些数据表明，GFRA1在人类肠道神经发生中的作用仍有待阐明，并且肠道中的RET信号传导可能通过其他途径发生，例如最近描述的与GDNF相关的分子神经营养素及其GFRA1样共受体GFRA2。
