Neu-Laxova Syndrome Is a Heterogeneous Metabolic Disorder Caused by Defects in Enzymes of the L-Serine Biosynthesis Pathway
Neu-Laxova Syndrome Is a Heterogeneous Metabolic Disorder Caused by Defects in Enzymes of the L-Serine Biosynthesis Pathway
复制标题
DOI：
10.1016/j.ajhg.2014.07.012
复制
发表时间：
2014-09-04
影响因子：
9.8
通讯作者：
Zenker, Martin
中科院分区：
文献类型：
--
作者：
Acuna-Hidalgo, Rocio;Schanze, Denny;Zenker, Martin
Neu-Laxova 综合征 (NLS) 是一种罕见的常染色体隐性遗传疾病，其特征是可识别的严重畸形模式，导致产前或产后早期死亡。 PHGDH（参与 L-丝氨酸生物合成第一步和限制步骤的基因）的纯合突变最近被确定为三个家族的疾病原因。通过研究受 NLS 影响的 12 个不相关家庭的队列，我们提供了证据，证明 NLS 具有遗传异质性，并且可能是由编码 L-丝氨酸生物合成途径酶的所有三个基因突变引起的。与最近报道的发现一致，我们可以在我们队列的三个不相关的家族中识别出 PHGDH 错义突变。此外，我们在四个近亲家族中绘制了包含 PSAT1 的重叠纯合染色体 9 区域。该基因编码磷酸丝氨酸转氨酶，这是 L-丝氨酸生物合成第二步的酶。我们鉴定了六个具有三种不同错义和移码 PSAT1 突变的家族，这些突变与该疾病完全分离。在另一个家族中，我们在 PSPH（编码磷酸丝氨酸磷酸酶的基因）中发现了纯合移码突变，该基因催化 L-丝氨酸生物合成的最后一步。有趣的是，所有三个已鉴定的基因之前都与丝氨酸缺乏症有关，其特征是神经系统表现各异。我们的研究结果扩展了我们对 NLS 作为 L-丝氨酸生物合成途径疾病的理解，并表明 NLS 代表了丝氨酸缺乏性疾病的严重结局，表明某些以早期致死为特征的复杂综合征确实可能是已知疾病表型谱的极端。
Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by a recognizable pattern of severe malformations leading to prenatal or early postnatal lethality. Homozygous mutations in PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis, were recently identified as the cause of the disease in three families. By studying a cohort of 12 unrelated families affected by NLS, we provide evidence that NLS is genetically heterogeneous and can be caused by mutations in all three genes encoding enzymes of the L-serine biosynthesis pathway. Consistent with recently reported findings, we could identify PHGDH missense mutations in three unrelated families of our cohort. Furthermore, we mapped an overlapping homozygous chromosome 9 region containing PSAT1 in four consanguineous families. This gene encodes phosphoserine aminotransferase, the enzyme for the second step in L-serine biosynthesis. We identified six families with three different missense and frameshift PSAT1 mutations fully segregating with the disease. In another family, we discovered a homozygous frameshift mutation in PSPH, the gene encoding phosphoserine phosphatase, which catalyzes the last step of L-serine biosynthesis. Interestingly, all three identified genes have been previously implicated in serine-deficiency disorders, characterized by variable neurological manifestations. Our findings expand our understanding of NLS as a disorder of the L-serine biosynthesis pathway and suggest that NLS represents the severe end of serine-deficiency disorders, demonstrating that certain complex syndromes characterized by early lethality could indeed be the extreme end of the phenotypic spectrum of already known disorders.