Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy
Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy
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DOI：
10.1093/hmg/9.1.109
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发表时间：
2000-01-01
影响因子：
3.5
通讯作者：
Hegele, RA
中科院分区：
文献类型：
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作者：
Cao, H;Hegele, RA
Dunnigan型家族性部分性脂肪营养不良(FPLD)患者出生时脂肪分布正常，但青春期后经历局部和进行性脂肪细胞变性，往往与严重的胰岛素抵抗和糖尿病相关。最近，FPLD基因被定位在染色体1q21-22上，该染色体含有编码核纤层蛋白A和C的LMNA基因，LMNA的突变被证明是常染色体显性遗传性EmeryDreifuss肌营养不良症(EDMD-AD)的基础，该疾病的特点是局部和进行性骨骼肌萎缩和心脏效应。我们假设EDMD-AD的局部肌肉萎缩和FPLD的局部脂肪细胞变性之间的相似性，以及它的染色体定位，使LMNA成为FPLD的一个很好的候选基因。对五个加拿大FPLD先证者的LMNA DNA测序表明，每个人都有一个新的错义突变R482Q，该突变与FPLD表型共分离，在2000个正常等位基因中缺失(P=1.1 x 10(-13))，这是首次报道导致脂肪组织退行性疾病的突变，表明LMNA突变可能是其他以组织类型和解剖部位特异性细胞变性为特征的疾病的基础。
Patients with Dunnigan-type familial partial lipodystrophy (FPLD) are born with normal fat distribution, but after puberty experience regional and progressive adipocyte degeneration, often associated with profound insulin resistance and diabetes. Recently, the FPLD gene was mapped to chromosome 1q21-22, which harbours the LMNA gene encoding nuclear lamins A and C, Mutations in LMNA were shown to underlie autosomal dominant EmeryDreifuss muscular dystrophy (EDMD-AD), which is characterized by regional and progressive skeletal muscle wasting and cardiac effects. We hypothesized that the analogy between the regional muscle wasting in EDMD-AD and the regional adipocyte degeneration in FPLD, in addition to its chromosomal localization, made LMNA a good candidate gene for FPLD, DNA sequencing of LMNA in five Canadian FPLD probands indicated that each had a novel missense mutation, R482Q, which co-segregated with the FPLD phenotype and was absent from 2000 normal alleles (P = 1.1 x 10(-13)), This is the first report of a mutation underlying a degenerative disorder of adipose tissue and suggests that LMNA mutations could underlie other diseases characterized by tissue type- and anatomical site-specific cellular degeneration.