Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome
Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome
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DOI：
10.1086/498852
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发表时间：
2006-01-01
影响因子：
9.8
通讯作者：
Matthijs, G
中科院分区：
文献类型：
--
作者：
Jaeken, J;Martens, K;Matthijs, G
在11例隐性先天性疾病患者中，我们将其称为“低紧张-胱氨酸尿综合征”，发现2p21染色体上的SLC3A1和PREPL基因部分微缺失。患者在出生时表现为全身性张力低下、肾结石、生长激素缺乏、轻度面部畸形和发育不良，随后在儿童期后期出现嗜食和体重迅速增加。由于已知SLC3A1的功能缺失突变会导致分离的I型胱氨酸尿症，并且由于侧翼基因C2orf34和PPM1B的表达正常，因此延长的表型可归因于PREPL的缺失。PREPL定位于细胞质中，与脯氨酸内肽酶和寡肽酶b具有同源性。用丙氨酸取代预测的催化残基（Ser470， Asp556和His601）导致与丝氨酸水解酶特异性探针的反应性丧失。与脯氨酰寡肽酶和寡肽酶B不同，它们的活性需要氨基端和羧基端序列，而PREPL的活性似乎只依赖于羧基端结构域。综上所述，这些结果表明，PREPL是一种新型的寡肽酶，具有独特的结构和功能特征，与低张力-胱氨酸尿综合征有关。
In 11 patients with a recessive congenital disorder, which we refer to as "the hypotonia-cystinuria syndrome," microdeletion of part of the SLC3A1 and PREPL genes on chromosome 2p21 was found. Patients present with generalized hypotonia at birth, nephrolithiasis, growth hormone deficiency, minor facial dysmorphism, and failure to thrive, followed by hyperphagia and rapid weight gain in late childhood. Since loss-of-function mutations in SLC3A1 are known to cause isolated cystinuria type I, and since the expression of the flanking genes, C2orf34 and PPM1B, was normal, the extended phenotype can be attributed to the deletion of PREPL. PREPL is localized in the cytosol and shows homology with prolyl endopeptidase and oligopeptidase B. Substitution of the predicted catalytic residues (Ser470, Asp556, and His601) by alanines resulted in loss of reactivity with a serine hydrolase-specific probe. In sharp contrast to prolyl oligopeptidase and oligopeptidase B, which require both aminoterminal and carboxyterminal sequences for activity, PREPL activity appears to depend only on the carboxyterminal domain. Taken together, these results suggest that PREPL is a novel oligopeptidase, with unique structural and functional characteristics, involved in hypotonia-cystinuria syndrome.