Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C
Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C
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DOI：
10.1086/302836
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发表时间：
2000-04-01
影响因子：
9.8
通讯作者：
Bowcock, AM
中科院分区：
文献类型：
--
作者：
Speckman, RA;Garg, A;Bowcock, AM
家族性部分脂肪营养不良(FPLD)是一种常染色体显性遗传性疾病，其特征是四肢和躯干的皮下脂肪组织显著丢失，但头部和颈部的脂肪沉积过多。这种疾病经常与严重的胰岛素抵抗、血脂异常和糖尿病有关。我们已经将FPLD的一个基因定位在染色体1q21-q23，最近有人提出在FPLD中核层蛋白A/C发生改变，这是基于在五个加拿大先证者中发现的一个新的错义突变(R482Q)。该基因在常染色体显性遗传性Emery-Dreifuss肌营养不良症(EDMD-AD)以及扩张型心肌病和传导系统疾病中已被证明是改变的。我们对15个FPLD家系进行了Lamin A/C突变检测，其中5个家系携带与疾病表型分离的R482Q改变。7个家系携带R482W突变，1个家系携带G465D突变。所有这些突变都存在于lamin A/C基因的第8外显子内，该外显子也被证明含有导致EDMD-AD的不同错义突变。在1个与染色体1q21-q23连锁的FPLD家系中，未能检测到lamin A/C突变。1个非典型FPLD家系在层蛋白A的第11外显子上存在R582H突变，该外显子不包含层蛋白C编码区的一部分。FPLD的所有突变都会影响Lamin A/C蛋白的球状C末端结构域。相反，导致扩张型心肌病和传导系统疾病的突变是在蛋白质的杆状结构域观察到的。FPLD突变R482Q和R482W出现在不同的单倍型上，表明它们可能不止一次出现。
Familial partial lipodystrophy (FPLD), Dunnigan variety, is an autosomal dominant disorder characterized by marked loss of subcutaneous adipose tissue from the extremities and trunk but by excess fat deposition in the head and neck. The disease is frequently associated with profound insulin resistance, dyslipidemia, and diabetes. We have localized a gene for FPLD to chromosome 1q21-q23, and it has recently been proposed that nuclear lamin A/C is altered in FPLD, on the basis of a novel missense mutation (R482Q) in five Canadian probands. This gene had previously been shown to be altered in autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD) and in dilated cardiomyopathy and conduction-system disease. We examined 15 families with FPLD for mutations in lamin A/C. Five families harbored the R482Q alteration that segregated with the disease phenotype. Seven families harbored an R482W alteration, and one family harbored a G465D alteration. All these mutations lie within exon 8 of the lamin A/C gene-an exon that has also been shown to harbor different missense mutations that are responsible for EDMD-AD. Mutations could not be detected in lamin A/C in one FPLD family in which there was linkage to chromosome 1q21-q23. One family with atypical FPLD harbored an R582H alteration in exon 11 of lamin A. This exon does not comprise part of the lamin C coding region. All mutations in FPLD affect the globular C-terminal domain of the lamin A/C protein. In contrast, mutations responsible for dilated cardiomyopathy and conduction-system disease are observed in the rod domain of the protein. The FPLD mutations R482Q and R482W occurred on different haplotypes, indicating that they are likely to have arisen more than once.