Defects in serine biosynthesis resulting from loss of function mutations in PHGDH , PSAT1, and PSPH cause a set of rare, autosomal recessive diseases known as Neu‐Laxova syndrome (NLS) or serine‐deficiency disorders. The diseases present with a broad range of phenotypes including lethality, severe neurological manifestations, seizures, and intellectual disability. However, because L‐serine supplementation, especially if started prenatally, can ameliorate and in some cases even prevent symptoms, knowledge of pathogenic variants is medically actionable. Here, we describe a functional assay that leverages the evolutionary conservation of an enzyme in the serine biosynthesis pathway, phosphoserine aminotransferase, and the ability of the human protein‐coding sequence (PSAT1 ) to functionally replace its yeast ortholog (SER1 ). Results from our quantitative, yeast‐based assay agree well with clinical annotations and expectations based on the disease literature. Using this assay, we have measured the functional impact of the 199 PSAT1 variants currently listed in ClinVar, gnomAD, and the literature. We anticipate that the assay could be used to comprehensively assess the functional impact of all SNP‐accessible amino acid substitution mutations in PSAT1 , a resource that could aid variant interpretation and identify potential NLS carriers.

中文翻译：

---

基于酵母的互补测定阐明了人 PSAT1 中 200 个错义变体的功能影响。

PHGDH、PSAT1和PSPH功能突变缺失导致丝氨酸生物合成缺陷，导致一系列罕见的常染色体隐性遗传疾病，称为 Neu-Laxova 综合征 (NLS) 或丝氨酸缺乏症。这些疾病具有广泛的表型，包括致命性、严重的神经系统表现、癫痫发作和智力障碍。然而，由于 L-丝氨酸补充剂（尤其是在产前开始）可以改善甚至在某些情况下预防症状，因此致病变异的知识在医学上是可行的。在这里，我们描述了一种功能测定，该测定利用丝氨酸生物合成途径中酶（磷酸丝氨酸转氨酶）的进化保守性，以及人类蛋白质编码序列（PSAT1 ）在功能上取代其酵母直系同源物（SER1）的能力。我们基于酵母的定量检测结果与基于疾病文献的临床注释和预期非常吻合。使用此测定，我们测量了ClinVar、gnomAD 和文献中当前列出的199 个PSAT1变体的功能影响。我们预计该测定可用于全面评估PSAT1中所有 SNP 可及的氨基酸取代突变的功能影响，这是一种可以帮助变异解释和识别潜在 NLS 携带者的资源。