Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease.
Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease.
复制标题
急性间歇性卟啉症：HMBS变体的预测致病性表明常染色体显性疾病的渗透率极低。
DOI：
10.1002/humu.23067
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发表时间：
2016-11
期刊：
影响因子：
3.9
通讯作者：
Desnick RJ
中科院分区：
文献类型：
--
作者：
Chen B;Solis-Villa C;Hakenberg J;Qiao W;Srinivasan RR;Yasuda M;Balwani M;Doheny D;Peter I;Chen R;Desnick RJ
急性间歇性卟啉症是由羟甲基胆烷合酶（HMBS）突变引起的，该突变显著降低了HMBS的酶活性。当杂合子发生危及生命的急性发作时，这种显性疾病被诊断出来，而大多数杂合子保持无症状和未确诊。虽然已经报道了>400个HMBS突变，但是致病性HMBS突变在基因组/外显子组数据库中的流行率以及实际疾病的发病率是未知的。因此，我们询问了基因组/外显子组数据库，在不同的人口/种族群体中鉴定了非同义变体（NSV）和共有剪接位点变体（CSSV），并通过预测算法和体外表达测定确定了NSV的致病性。高加索人最多：在约92，000个等位基因中有58个NSV和2个CSSV，组合等位基因频率为0.00575。计算机模拟算法预测14/58例NSV为“可能致病”。体外表达鉴定出10/58个NSV可能是致病性的（计算机模拟预测7个），其与两个CSSV一起具有0.00056的组合等位基因频率。值得注意的是，人类基因突变数据库中的六个可能致病的突变/NSV是良性的。与最近有症状的欧洲杂合子的患病率估计值（~0.000005）相比，高加索人中可能致病的HMBS突变的患病率更频繁>100倍。因此，急性发作的估计发病率约为具有可能致病突变的杂合子的1%，突出了诱发/保护基因和环境修饰剂的重要性，这些基因和环境修饰剂促进/预防了发作。
Acute Intermittent Porphyria results from hydroxymethylbilane synthase (HMBS) mutations that markedly decrease HMBS enzymatic activity. This dominant disease is diagnosed when heterozygotes have life-threatening acute attacks, while most heterozygotes remain asymptomatic and undiagnosed. Although >400 HMBS mutations have been reported, the prevalence of pathogenic HMBS mutations in genomic/exomic databases, and the actual disease penetrance are unknown. Thus, we interrogated genomic/exomic databases, identified non-synonymous variants (NSVs) and consensus splice-site variants (CSSVs) in various demographic/racial groups, and determined the NSV’s pathogenicity by prediction algorithms and in vitro expression assays. Caucasians had the most: 58 NSVs and two CSSVs among ~92,000 alleles, a 0.00575 combined allele frequency. In silico algorithms predicted 14/58 NSVs as “likely-pathogenic”. In vitro expression identified 10/58 NSVs as likely-pathogenic (seven predicted in silico), which together with two CSSVs had a combined allele frequency of 0.00056. Notably, six presumably pathogenic mutations/NSVs in the Human Gene Mutation Database were benign. Compared to the recent prevalence estimate of symptomatic European heterozygotes (~0.000005), the prevalence of likely-pathogenic HMBS mutations among Caucasians was >100 times more frequent. Thus, the estimated penetrance of acute attacks was ~1% of heterozygotes with likely-pathogenic mutations, highlighting the importance of predisposing/protective genes and environmental modifiers that precipitate/prevent the attacks.