Teresa Esposito, Lonardo Fortunato, Fiumara Agata, Lombardi Cinzia, Russo Paola, Zuppi Cecilia, Scarano Gioacchino, Musumeci Salvatore, Gianfrancesco Fernando
Institute of Food Science, Italian National Research Council, Avellino, Italy; Neurogenetics Unit, IRCCS Neuromed, Pozzilli, Isernia, Italy.
Mol Genet Metab. 2006 Jun;88(2):192-5. doi: 10.1016/j.ymgme.2006.02.014. Epub 2006 Apr 4.
Fish-odor syndrome or trimethylaminuria, is a rare inborn error of metabolism inherited in an autosomal recessive fashion, involving the dysfunction of hepatic enzyme flavin-containing monooxygenase 3 (FMO3) that converts fishy-smelling trimethylamine (TMA) into odorless trimethylamine-N-oxide (TMAO). This confers, to the affected individual a very unpleasant body odor resembling that of rotting fish. This disorder has been relatively well-documented in British, Australian, and American populations and reports have appeared regarding patients in Thailand and Hong Kong, but no Italian families affected by trimethylaminuria have been reported in the literature. We have collected a cohort of Italian families and investigated the genetic basis of the disorder in these Italian pedigrees disclosing a spectrum of molecular variation in the FM03 gene comprising three novel deleterious mutations: the first documented de novo missense mutation causative of trimethylaminuria; a guanidine nucleotide deletion (G1182del) at codon 394 and a novel missense mutation (R238P) that altered highly conserved amino acid in the exon 6. Moreover, we investigated by aplotype analysis a family with mild TMAuria identifying a putative causative aplotype. Finally, we failed to detect any variation in other Italian families suggesting that this gene is not associated with all clinical form of trimethylaminuria or that polymorphisms in this gene could be susceptibility factors for developing the disease. Our findings support the hypothesis that TMAuria is not a rare recessive disorder but rather a spectrum of malodour phenotypes in which diet and environmental exposures can play a role in triggering symptoms.
鱼腥味综合征或三甲胺尿症，是一种罕见的常染色体隐性遗传代谢性先天性疾病，涉及肝脏中含黄素单加氧酶3（FMO3）功能异常，该酶可将有鱼腥味的三甲胺（TMA）转化为无气味的氧化三甲胺（TMAO）。这使得患病个体身上散发出非常难闻的类似腐鱼的体味。这种疾病在英国、澳大利亚和美国人群中有相对充分的文献记载，也有关于泰国和香港患者的报道，但文献中尚未报道过受三甲胺尿症影响的意大利家庭。我们收集了一组意大利家庭，并对这些意大利家系中该疾病的遗传基础进行了研究，发现FMO3基因存在一系列分子变异，包括三个新的有害突变：第一个记录在案的导致三甲胺尿症的新发错义突变；密码子394处的鸟嘌呤核苷酸缺失（G1182del）以及一个新的错义突变（R238P），该突变改变了外显子6中高度保守的氨基酸。此外，我们通过单倍型分析研究了一个患有轻度三甲胺尿症的家庭，确定了一个可能的致病单倍型。最后，我们在其他意大利家庭中未检测到任何变异，这表明该基因并非与所有三甲胺尿症临床类型相关，或者该基因中的多态性可能是引发该疾病的易感因素。我们的研究结果支持这样一种假设，即三甲胺尿症并非罕见的隐性疾病，而是一系列恶臭表型，其中饮食和环境暴露可能在引发症状方面发挥作用。
