Zeynalzadeh Monica, Tafazoli Alireza, Aarabi Azadeh, Moghaddassian Morteza, Ashrafzadeh Farah, Houshmand Massoud, Taghehchian Negin, Abbaszadegan Mohammad Reza
Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
J Pediatr Endocrinol Metab. 2018 Jan 26;31(2):205-212. doi: 10.1515/jpem-2017-0305.
Maple syrup urine disease (MSUD) is a rare metabolic autosomal recessive disorder caused by dysfunction of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex. Mutations in the BCKDHA, BCKDHB and DBT genes are responsible for MSUD. The current study analyzed seven Iranian MSUD patients genetically and explored probable correlations between their genotype and phenotype.
The panel of genes, including BCKDHA, BCKDHB and DBT, was evaluated, using routine the polymerase chain reaction (PCR)-sequencing method. In addition, protein modeling (homology and threading modeling) of the deduced novel mutations was performed. The resulting structures were then analyzed, using state-of-the-art bioinformatics tools to better understand the structural and functional effects caused by mutations.
Seven mutations were detected in seven patients, including four novel pathogenic mutations in BCKDHA (c.1198delA, c.629C>T), BCKDHB (c.652C>T) and DBT (c.1150A>G) genes. Molecular modeling of the novel mutations revealed clear changes in the molecular energy levels and stereochemical traits of the modeled proteins, which may be indicative of strong correlations with the functional modifications of the genes. Structural deficiencies were compatible with the observed phenotypes.
Any type of MSUD can show heterogeneous clinical manifestations in different ethnic groups. Comprehensive molecular investigations would be necessary for differential diagnosis.
枫糖尿症（MSUD）是一种罕见的常染色体隐性遗传代谢紊乱疾病，由支链α-酮酸脱氢酶（BCKDH）复合体功能障碍引起。BCKDHA、BCKDHB和DBT基因的突变是导致MSUD的原因。本研究对7例伊朗MSUD患者进行了基因分析，并探讨了其基因型与表型之间可能的相关性。
采用常规聚合酶链反应（PCR）测序方法对包括BCKDHA、BCKDHB和DBT在内的基因进行评估。此外，对推导的新突变进行了蛋白质建模（同源建模和穿线建模）。然后使用最先进的生物信息学工具对所得结构进行分析，以更好地理解突变引起的结构和功能影响。
在7例患者中检测到7个突变，包括BCKDHA基因中的4个新的致病突变（c.1198delA、c.629C>T）、BCKDHB基因中的（c.652C>T）和DBT基因中的（c.1150A>G）。新突变的分子建模显示，建模蛋白质的分子能量水平和立体化学特征发生了明显变化，这可能表明与基因的功能修饰有很强的相关性。结构缺陷与观察到的表型相符。
任何类型的MSUD在不同种族中都可能表现出异质性临床表现。进行全面的分子研究对于鉴别诊断是必要的。
