LONG-SEGMENT AND SHORT SEGMENT FAMILIAL HIRSCHSPRUNGS-DISEASE - VARIABLE CLINICAL EXPRESSION AT THE RET LOCUS
LONG-SEGMENT AND SHORT SEGMENT FAMILIAL HIRSCHSPRUNGS-DISEASE - VARIABLE CLINICAL EXPRESSION AT THE RET LOCUS
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DOI：
10.1136/jmg.31.8.602
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发表时间：
1994-08-01
影响因子：
4
通讯作者：
LYONNET, S
中科院分区：
文献类型：
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作者：
EDERY, P;PELET, A;LYONNET, S
先天性巨结肠症（神经节巨结肠，HSCR）是一种常见的原因不明的疾病（1/5000 活产儿），导致新生儿肠梗阻以及婴儿和成人严重便秘。在大多数病例（80%）中，无神经节束仅涉及直肠和乙状结肠（短段 HSCR），而在 20% 的病例中，它延伸至结肠近端（长段 HSCR）。在之前的一项研究中，我们将长片段家族性 HSCR 的基因定位到 10 号染色体的近端长臂 (10q11.2)。家族性 HSCR 的进一步连锁分析表明，该疾病基因与映射到染色体 10q11.2 的 RET 原癌基因紧密连锁。最近，在 HSCR 患者中发现了 RET 无义和错义突变。然而，RET基因突变是否同时导致长片段和短片段家族性HSCR的问题仍然没有答案。我们利用10q染色体的微卫星DNA标记对11个长片段HSCR家族和8个短片段HSCR家族进行了遗传连锁分析。在两种解剖形式中，在 RET 原癌基因位点和疾病位点之间观察到紧密的成对连锁，没有重组事件（对于短片段和长片段 HSCR，分别在 0 = 0% 时，Zmax = 2.16 和 Zmax = 5.38）。在两组中进行的多点连锁分析表明最大似然估计位于 RET 位点。此外，我们发现 RET 原癌基因的点突变发生在长片段或短片段 HSCR 家族中，并且我们为引起突变的疾病的不完全外显提供了证据。这些数据表明，根据临床和遗传标准分开的家族性 HSCR 的两种解剖形式，可以被视为 RET 位点突变的可变临床表达。
Hirschsprung's disease (aganglionic megacolon, HSCR) is a frequent condition of unknown origin (1/5000 live births) resulting in intestinal obstruction in neonates and severe constipation in infants and adults. In the majority of cases (80%), the aganglionic tract involves the rectum and the sigmoid colon only (short segment HSCR), while in 20% of cases it extends toward the proximal end of the colon (long segment HSCR). In a previous study, we mapped a gene for long segment familial HSCR to the proximal long arm of chromosome 10 (10q11.2). Further linkage analyses in familial HSCR have suggested tight linkage of the disease gene to the RET protooncogene mapped to chromosome 10q11.2. Recently, nonsense and missense mutations of RET have been identified in HSCR patients. However, the question of whether mutations of the RET gene account for both long segment and short segment familial HSCR remained unanswered.We have performed genetic linkage analyses in 11 long segment HSCR families and eight short segment HSCR families using microsatellite DNA markers of chromosome 10q. In both anatomical forms, tight pairwise linkage with no recombinant events was observed between the RET proto-oncogene locus and the disease locus (Zmax = 2.16 and Zmax=5.38 for short segment and long segment HSCR respectively at 0=0%). Multipoint linkage analyses performed in the two groups showed that the maximum likelihood estimate was at the RET locus. Moreover, we show that point mutations of the RET proto-oncogene occur either in long segment or in short segment HSCR families and we provide evidence for incomplete penetrance of the disease causing mutation. These data suggest that the two anatomical forms of familial HSCR, which have been separated on the basis of clinical and genetic criteria, may be regarded as the variable clinical expression of mutations at the RET locus.