Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome
Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome
复制标题
DOI：
10.1038/ejhg.2008.15
复制
发表时间：
2008-07-01
影响因子：
5.2
通讯作者：
Dode, Catherine
中科院分区：
文献类型：
--
作者：
Leroy, Chrystel;Fouveaut, Corinne;Dode, Catherine
卡尔曼综合征是一种发育性疾病，合并低促性腺激素性性腺功能减退和嗅觉丧失。PROKR 2或PROK 2（分别编码前动力蛋白受体-2（G蛋白偶联受体）及其配体之一前动力蛋白-2）的推定功能丧失突变最近已在约10%的卡尔曼综合征受影响个体中报告。值得注意的是，给定的PROKR 2突变在患者的杂合、纯合或复合杂合状态中被发现，因此提出了在杂合患者中疾病的可能的双基因遗传的问题。事实上，其中一名患者还携带了KAL 1的错义突变，KAL 1是导致X染色体连锁型卡尔曼综合征的基因。然而，到目前为止，PROK 2中的突变仅在杂合状态中被发现。在这里，我们报告了PROK 2双等位基因突变的鉴定，即错义突变p.R73C和移码突变c。163 delA，在273例散发病例中的2例中。我们的结论是，PROK 2纯合状态的突变占少数情况下卡尔曼综合征。此外，由于相同的R73 C突变先前在杂合状态下被报道，并且由于Prok 2敲除小鼠仅在纯合状态下表现出异常表型，因此我们预测携带PROK 2单等位基因突变的患者具有另一种致病突变，推测是在尚未发现的卡尔曼综合征基因中。
Kallmann syndrome is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Putative loss-of-function mutations in PROKR2 or PROK2, encoding prokineticin receptor-2 (a G protein-coupled receptor), and one of its ligands, prokineticin-2, respectively, have recently been reported in approximately 10% of Kallmann syndrome affected individuals. Notably, given PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state in patients, thus raising the question of a possible digenic inheritance of the disease in heterozygous patients. Indeed, one of these patients was also carrying a missense mutation in KAL1, the gene responsible for the X chromosome-linked form of Kallmann syndrome. Mutations in PROK2, however, have so far been found only in the heterozygous state. Here, we report on the identification of PROK2 biallelic mutations, that is, a missense mutation, p. R73C, and a frameshift mutation, c. 163delA, in two out of 273 patients presenting as sporadic cases. We conclude that PROK2 mutations in the homozygous state account for a few cases of Kallmann syndrome. Moreover, since the same R73C mutation was previously reported in the heterozygous state, and because Prok2 knockout mice exhibit an abnormal phenotype only in the homozygous condition, we predict that patients carrying monoallelic mutations in PROK2 have another disease-causing mutation, presumably in still undiscovered Kallmann syndrome genes.