Occasionally, different mutations in a single gene can give rise to different phenotypes. An example of this is provided by different mutations in the cystic fibrosis gene, CFTR. Mutations in CFTR have been found in otherwise healthy males with infertility caused by congenital bilateral absence of the vas deferens (CBAVD). These patients do not have other features of cystic fibrosis such as pulmonary or pancreatic disease. However, the vast majority of males with typical cystic fibrosis have CBAVD, so isolated CBAVD arising from CFTR mutations represents a very restricted expression of the cystic fibrosis phenotype.
A more striking example is seen in Hirschsprung's disease, which is characterized by failure of development of autonomic ganglia in the large bowel, leading to intestinal obstruction or impaired bowel motility in infants. Some patients with Hirschsprung's disease have mutations in the RET proto-oncogene (17). Mutations in RET are also seen in families with the familial cancer syndromes multiple endocrine neoplasia (MEN), types 2A and 2B (see Chap. 6). Therefore, mutations in a single gene, RET, are associated with diseases as seemingly unrelated as Hirschsprung's disease and MEN 2.
A final example of mutations in a single gene causing different diseases is seen with mutations in the lamin A/C gene, LMNA, on chromosome 1q. This gene encodes lamin A and C proteins that are produced by alternative splicing of a common transcript. These proteins associate with chromatin and other proteins in the inner nuclear membrane. Different mutations in LMNA give rise to Emery-Dreifus muscular dystrophy, type I (EMD1), which is an X-linked form of muscular dystrophy associated with cardiac conduction abnormalities; EMD2, which is an autosomal recessive form of the disease; a familial cardiomyopathy syndrome known as CMD1A; a form of lipodystrophy known as familial partial lipodys-trophy, which is characterized by loss of fat in the extremities and accumulation of fat around the face and neck, and which shows an autosomal dominant inheritance pattern; and, finally, a recessive form of Charcot-Marie-Tooth disease, CMT2A (18,19). This extraordinary range of phenotypes from mutations in the one gene is probably an effect of mutations in different functional domains of the lamin A/C protein.
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