Hutchinson-Gilford Progeria Syndrom--Genetic Aging Model

哈钦森-吉尔福德早衰综合症--遗传衰老模型

• 批准号: 6829371
• 负责人: FRANCIS S. COLLINS
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6829371
• 关键词: disease /disorder model; genetic library; genetic models; laboratory mouse; lamins; model design /development; point mutation; premature aging; protein structure

Hutchinson-Gilford progeria syndrome (HGPS) is the most dramatic human syndrome of premature aging. Children with this rare condition are normal at birth, but by age 2 they have stopped growing, lost their hair, and shown skin changes and loss of subcutaneous tissue that resemble the ravages of old age. They rarely live past adolescence, dying almost always of advanced cardiovascular disease (heart attack and stroke). The classic syndrome has never been observed to recur in families. Using a genome-wide analysis for homozygosity, we discovered three unique cases of HGPS with either segmental uniparental isodisomy or an interstitial deletion, all involving chromosome 1q. Sequencing a plausible candidate gene in the minimal interval, the gene for lamin A/C (LMNA), we discovered that nearly all cases of HGPS harbor a de novo point mutation in codon 608 of the LMNA gene. Subsequent experiments showed that this mutation causes disease by creating an abnormal splice donor, generating a mRNA with an internal deletion of 150 nt. This is translated into a mutant form of the lamin A protein (referred to now as progerin) that lacks 50 amino acids near the C-terminus, and apparently acts as a potent dominant negative, disrupting the structure of the nuclear lamina. Once having identified the genetic basis for this disease, we have turned our attention to generating a mouse model. A number of different transgenes for wildtype or mutant lamin A have been constructed and injected into mouse oocytes. Liveborn animals have been obtained, and detailed analysis of their phenotypes is just beginning. We are also tagging the wildtype and mutant protein at the amino-terminal end, in order to follow its fate in the nucleus of transfected cells. We also hypothesize that other structural or regulatory variants in the LMNA gene might actually be protective against the normal aging process. Accordingly, we are developing a detailed catalog of variants in the vicinity of the gene, and testing those in well-matched cohorts of controls and individuals who have achieved exceptional longevity.

Hutchinson-Gilford Progeria综合征（HGP）是早熟的最戏剧性人类综合征。出生时这种罕见状况的孩子正常，但是到2岁时，他们已经停止生长，失去头发，表现出皮肤变化和皮下组织的丧失，类似于老年的破坏。他们很少生活过青春期，几乎总是死于晚期心血管疾病（心脏病发作和中风）。从未发现经典综合征在家庭中复发。使用全基因组分析的纯合性分析，我们发现了三个独特的HGP病例，具有节段的单亲异构疾病或间质缺失，均涉及1q染色体。在最小间隔（LMNA）的最小间隔（LMNA）中测序了合理的候选基因，我们发现几乎所有HGP的HGPS病例都具有LMNA基因密码子608中的从头突变。随后的实验表明，该突变通过产生异常的剪接供体来引起疾病，并产生内部缺失150 nt的mRNA。这被翻译成层粘连蛋白A蛋白的突变形式（现在称为孕激素），该蛋白在C末端附近缺乏50个氨基酸，并且显然充当有效的显性负阴性，破坏了核层的结构。 一旦确定了这种疾病的遗传基础，我们就将注意力转向产生小鼠模型。许多用于野生型或突变层粘连蛋白A的不同转基因已构造并注入小鼠卵母细胞。已经获得了活动物，对其表型的详细分析才开始。我们还在氨基末端标记野生型和突变蛋白，以遵循其在转染细胞核中的命运。我们还假设LMNA基因中的其他结构或调节变体实际上可能针对正常的衰老过程具有保护作用。因此，我们正在开发基因附近变体的详细目录，并测试那些在匹配的对照组和实现出色寿命的个人中的人群。