Klaassen K, Djordjevic M, Skakic A, Kecman B, Drmanac R, Pavlovic S, Stojiljkovic M
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic", Belgrade, Serbia.
Mol Genet Metab Rep. 2021 Nov 19;29:100822. doi: 10.1016/j.ymgmr.2021.100822. eCollection 2021 Dec.
Phenylketonuria (PKU) is an inborn error of metabolism caused by variants in the phenylalanine hydroxylase () gene and it is characterized by excessively high levels of phenylalanine in body fluids. PKU is a paradigm for a genetic disease that can be treated and majority of developed countries have a population-based newborn screening. Thus, the combination of early diagnosis and immediate initiation of treatment has resulted in normal intelligence for treated PKU patients. Although PKU is a monogenic disease, decades of research and clinical practice have shown that the correlation between the genotype and corresponding phenotype is not simple at all. Attempts have been made to discover modifier genes for PKU cognitive phenotype but without any success so far. We conducted whole genome sequencing of 4 subjects from unrelated non-consanguineous families who presented with pathogenic mutations in the gene, high blood phenylalanine concentrations and near-normal cognitive development despite no treatment. We used cross sample analysis to select genes common for more than one patient. Thus, the gene family emerged as the only relevant gene family with variants detected in 3 of 4 analyzed patients. We detected two novel variants, p.Pro1591Ala in and p.Asp18Asn in , as well as :p.Gly46Ser, :p.Pro1388_Phe1389insLeuPro and :p.Pro1716Thr variants that were previously described. Computational analysis indicated that the identified variants do not abolish the function of SHANK proteins. However, changes in posttranslational modifications of SHANK proteins could influence functioning of the glutamatergic synapses, cytoskeleton regulation and contribute to maintaining optimal synaptic density and number of dendritic spines. Our findings are linking gene family and brain plasticity in PKU for the first time. We hypothesize that variant SHANK proteins maintain optimal synaptic density and number of dendritic spines under high concentrations of phenylalanine and could have protective modifying effect on cognitive development of PKU patients.
苯丙酮尿症（PKU）是一种由苯丙氨酸羟化酶（PAH）基因突变引起的先天性代谢缺陷疾病，其特征是体液中苯丙氨酸水平过高。PKU是一种可治疗的遗传疾病范例，大多数发达国家都开展了基于人群的新生儿筛查。因此，早期诊断并立即开始治疗使得接受治疗的PKU患者能够拥有正常智力。尽管PKU是一种单基因疾病，但数十年的研究和临床实践表明，基因型与相应表型之间的相关性一点也不简单。人们曾试图寻找PKU认知表型的修饰基因，但迄今为止没有任何成功。我们对来自无关非近亲家庭的4名受试者进行了全基因组测序，这些受试者的PAH基因存在致病突变，血液苯丙氨酸浓度高，但未经治疗却有接近正常的认知发育。我们使用交叉样本分析来选择多名患者共有的基因。因此，SHANK基因家族成为唯一在4名分析患者中的3名患者中检测到变异的相关基因家族。我们检测到两个新变异，PAH基因中的p.Pro1591Ala和SHANK3基因中的p.Asp18Asn，以及先前已描述的SHANK2基因的:p.Gly46Ser、:p.Pro1388_Phe1389insLeuPro和:p.Pro1716Thr变异。计算分析表明，所鉴定的变异并未消除SHANK蛋白的功能。然而，SHANK蛋白翻译后修饰的变化可能会影响谷氨酸能突触的功能、细胞骨架调节，并有助于维持最佳的突触密度和树突棘数量。我们的研究结果首次将SHANK基因家族与PKU中的脑可塑性联系起来。我们假设，变异的SHANK蛋白在高苯丙氨酸浓度下维持最佳的突触密度和树突棘数量，并可能对PKU患者的认知发育具有保护性修饰作用。
