Clinical utility gene card for: Trimethylaminuria - update 2014.
Clinical utility gene card for: Trimethylaminuria - update 2014.
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DOI：
10.1038/ejhg.2014.226
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发表时间：
2015-09
期刊：
影响因子：
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通讯作者：
Phillips IR
中科院分区：
文献类型：
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作者：
Shephard EA;Treacy EP;Phillips IR
据报道，FMO 3基因的30多个序列变体可引起三甲基氨基尿。大多数是错义变体，但无义变体，小（1-或2-bp）缺失和一个大（12.2-kb）缺失已被报道。本文报道的变体描述基于基因组参考序列NG_012690。1和转录物参考序列NM_001002294。2.致病序列变异是群体特异性的。迄今为止最常见的是C。458 C> T（p.（Pro 153 Leu））1和c. 913G> T（p.（Glu 305 *）），2个在欧洲种族的个体中，和c. 613 C> T（p.（Arg 205 Cys））3和c. 1498 C> T（p.（Arg 500 *）），日语4。在一种情况下，变异发生的单倍型是重要的：c. 560 T> C（p.（Val 187 Ala））对FMO 3活性没有影响，但当它与常见的多态性变体c顺式发生时，472G> A（p.（Glu 158 Lys）），严重影响酶的活性。5已经建立了人FMO 3数据库6（http：//databases.com）。爱。nl/shared/genes/FMO 3）和迄今为止鉴定的致病序列变体。7-9除了罕见的致病性变体外，还鉴定了FMO 3的15种非同义单核苷酸多态性（SNP）变体。10个，只有一个，C。183C> A（p.（Asn 61 Lys）），其以低频率发生，导致酶活性的严重降低。11然而，一些多态变体，例如，c. 472G> A（p.（Glu 158 Lys））和c. 923A> G（p.（Glu 308 Gly）），当以顺式存在时，可引起酶活性的适度降低。10，12当以纯合子状态存在时，它们可能导致轻度或短暂的三甲基氨基尿，特别是在FMO 3表达低的婴儿和幼儿中。15已报道含有启动子区域SNP变体的两种FMO 3单倍型在体外严重降低表达。[16]尽管这些单倍型在体内的影响尚未得到证实，但它们可能在缺乏编码区变异的情况下导致了这种疾病。其他四种单倍型在体外适度降低表达，17是g.− 5109 G> C SNP变体存在的结果。虽然四种单倍型中没有一种对体内的三甲胺（TMA）代谢有显著影响，但它们可能导致更中度的疾病。
More than 30 sequence variants of the FMO3 gene have been reported to cause trimethylaminuria. Most are missense variants, but nonsense variants, small (1-or 2-bp) deletions and one large (12.2-kb) deletion have been reported. Variant descriptions reported here are on the basis of the genomic reference sequence NG_012690. 1 and the transcript reference sequence NM_001002294. 2. Causative sequence variants are population specific. The most common identified to date are c. 458C> T (p.(Pro153Leu)) 1 and c. 913G> T (p.(Glu305*)), 2 in individuals of European ethnicity, and c. 613C> T (p.(Arg205Cys)) 3 and c. 1498C> T (p.(Arg500*)), 4 in Japanese. In one case, the haplotype in which a variant occurs is important: c. 560T> C (p.(Val187Ala)) has no effect on FMO3 activity, but when it occurs in cis with the common polymorphic variant c. 472G> A (p.(Glu158Lys)) it severely affects enzyme activity. 5 A human FMO3 database has been established6 (http://databases. lovd. nl/shared/genes/FMO3) and causative sequence variants identified to date have been reported. 7–9 In addition to rare causative variants, 15 nonsynonymous singlenucleotide polymorphic (SNP) variants of FMO3 have been identified. 10 Of these, only one, c. 183C> A (p.(Asn61Lys)), which occurs at low frequency, results in a severe reduction of enzyme activity. 11 However, some polymorphic variants, for example, c. 472G> A (p.(Glu158Lys)) and c. 923A> G (p.(Glu308Gly)), when present in cis, can cause a moderate decrease in enzyme activity. 10, 12 When present in the homozygous state, they may cause mild or transient trimethylaminuria, particularly in infants and young children, 13, 14 who have low expression of FMO3. 15 Two FMO3 haplotypes that contain promoter-region SNP variants have been reported to severely reduce expression in vitro. 16 Although the impact of these haplotypes in vivo has not been validated, it is possible that they contribute to the disorder in the absence of coding-region variants. Four other haplotypes moderately reduce expression in vitro, 17 a consequence of the presence of a g.− 5109G> C SNP variant. Although none of the four haplotypes has a marked effect on the metabolism of trimethylamine (TMA) in vivo, 17 it is possible that they contribute to more moderate forms of the disorder.