Compound heterozygosity for mutations in LMNA causes a Progeria syndrome without prelamin A accumulation
Compound heterozygosity for mutations in LMNA causes a Progeria syndrome without prelamin A accumulation
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DOI：
10.1093/hmg/ddl172
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发表时间：
2006-08-15
影响因子：
3.5
通讯作者：
van den Wijngaard, Arthur
中科院分区：
文献类型：
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作者：
Verstraeten, Valerie L. R. M.;Broers, Jos L. V.;van den Wijngaard, Arthur
lmna相关的类早衰综合征有显性和隐性遗传的报道。我们报告一个2岁的男孩，由于LMNA的复合杂合错义突变（p.T528M和p.M540T），明显具有典型的Hutchinson-Gilford早衰综合征（HGPS）。这两种突变都影响a型纤层蛋白c端球状结构域内的一个保守区域，定义了一个早衰热点。患者细胞核未见层前蛋白A积聚。总的来说，核表型与先前描述的HGPS不一致。相反，蜂窝状结构占主导地位，并且可以检测到b型层粘连蛋白表达减少或缺失的核泡。健康的杂合亲本也表现出类似的细胞核变化，但比例较小。用一种法尼基化抑制剂治疗导致核周围、环状核膜斑块和核膜内/跨核膜内陷的前层蛋白a积累。总之，这些发现表明C端球状层蛋白a /C区域在核结构中起关键作用，并支持异常组装对类早衰表型的主要贡献。与之前的建议相反，我们表明前纤层蛋白A积累不是早衰表型的主要决定因素。
LMNA-associated progeroid syndromes have been reported with both recessive and dominant inheritance. We report a 2-year-old boy with an apparently typical Hutchinson-Gilford progeria syndrome (HGPS) due to compound heterozygous missense mutations (p.T528M and p.M540T) in LMNA. Both mutations affect a conserved region within the C-terminal globular domain of A-type lamins, defining a progeria hot spot. The nuclei of the patient showed no prelamin A accumulation. In general, the nuclear phenotype did not correspond to that previously described for HGPS. Instead, honeycomb figures predominated and nuclear blebs with reduced/absent expression of B-type lamins could be detected. The healthy heterozygous parents showed similar nuclear changes, although in a smaller percentage of nuclei. Treatment with a farnesylation inhibitor resulted in accumulation of prelamin A at the nuclear periphery, in annular nuclear membrane plaques and in intra/trans-nuclear membrane invaginations. In conclusion, these findings suggest a critical role for the C-terminal globular lamin A/C region in nuclear structure and support a major contribution of abnormal assembly to the progeroid phenotype. In contrast to earlier suggestions, we show that prelamin A accumulation is not the major determinant of the progeroid phenotype.