Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I
Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I
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DOI：
10.1016/j.ajpath.2011.06.024
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发表时间：
2011-10-01
影响因子：
6
通讯作者：
Gillmore, Julian D.
中科院分区：
文献类型：
--
作者：
Rowczenio, Dorota;Dogan, Ahmet;Gillmore, Julian D.
遗传性载脂蛋白A-I淀粉样变性的表型是异质性的，一些患者在年轻成人时发生广泛的内脏淀粉样蛋白沉积和终末期肾衰竭，而另一些患者仅具有喉部和/或皮肤淀粉样蛋白，这可能几乎没有临床后果。系统性淀粉样变性患者的临床管理和预后完全取决于原纤维蛋白的正确鉴定，例如轻链淀粉样变性（AL，以前称为"原发性"），最常见的诊断类型，用化疗治疗，这在遗传性载脂蛋白A-I淀粉样变性中绝对没有作用。我们报告了五种新的载脂蛋白A-I变异体，其中四种是淀粉样变性的，其中一种是偶然发生在系统性AL淀粉样变性患者中。有趣的是，4例载脂蛋白A-I淀粉样变性患者中只有1例有类似疾病的家族史。激光显微切割和串联质谱为基础的蛋白质组学被用来确认淀粉样纤维蛋白，并首次在载脂蛋白A-I淀粉样变性，证明只有突变的蛋白质，而不是野生型载脂蛋白A-I沉积为淀粉样蛋白。遗传性载脂蛋白A-I淀粉样变性的临床谱和结果进行了详细的审查，并支持有明显的本地化淀粉样变性的IHC是nondiagnosis的原纤维蛋白，即使在没有家族病史的患者中的载脂蛋白A-I基因测序的需要。(Ant J Pathol 2011，179：1978 - 1987; DOI：10.10164/j.ajpath.2011.06.024）
The phenotype of hereditary apolipoprotein A-I amyloidosis is heterogeneous with some patients developing extensive visceral amyloid deposits and end-stage renal failure as young adults and others having only laryngeal and/or skin amyloid, which may be of little clinical consequence. Clinical management and prognosis of patients with systemic amyloidosis depend entirely on correct identification of the fibril protein, such that light chain amyloidosis (AL, previously referred to as "primary"), the most frequently diagnosed type, is treated with chemotherapy, which has absolutely no role in hereditary apolipoprotein A-I amyloidosis. We report five novel apolipoprotein A-I variants, four of which were amyloidogenic and one of which was incidental in a patient with systemic AL amyloidosis. Interestingly, only one of four patients with apolipoprotein A-I amyloidosis had a family history of similar disease. Laser microdissection and tandem mass spectrometry based proteomics were used to confirm the amyloid fibril protein and, for the first time in apolipoprotein A-I amyloidosis, demonstrated that only mutated protein as opposed to wild-type apolipoprotein A-I was deposited as amyloid. The clinical spectrum and outcome of hereditary apolipoprotein A-I amyloidosis are reviewed in detail and support the need for sequencing of the apolipoprotein A-I gene among patients with apparent localized amyloidosis in whom IHC is nondiagnostic of the fibril protein, even in the absence of a family history of disease. (Ant J Pathol 2011, 179:1978-1987; DOI: 10.10164/j.ajpath.2011.06.024)