FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies.
FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies.
复制标题
DOI：
10.1530/ec-15-0015
复制
发表时间：
2015-06
影响因子：
2.9
通讯作者：
Mendonca BB
中科院分区：
文献类型：
--
作者：
Correa FA;Trarbach EB;Tusset C;Latronico AC;Montenegro LR;Carvalho LR;Franca MM;Otto AP;Costalonga EF;Brito VN;Abreu AP;Nishi MY;Jorge AA;Arnhold IJ;Sidis Y;Pitteloud N;Mendonca BB
先天性垂体功能减退症（CH）的遗传病因尚未完全阐明。FGFR 1和PROKR 2功能丧失突变通常参与促性腺功能减退症（HH），然而，由于HH和CH的临床和遗传重叠，这些基因也可能参与CH的发病机制。使用候选基因的方法，我们筛选了156例巴西患者合并垂体激素缺乏症（CPHD）的FGFR 1和PROKR 2功能丧失突变。我们在4名无关患者（2名男性）中鉴定出3种FGFR 1变异体（p.Arg448Trp、p.Ser107Leu和p.Pro772Ser），在2名无关女性患者中鉴定出2种PROKR 2变异体（p.Arg85Cys和p.Arg248Glu）。五的六名患者窝藏的变异有一个一级亲属，是一个不受影响的载体it. Results的功能研究表明，新的FGFR 1变异p.Arg448Trp是一个功能丧失的变体，而p.Ser107Leu和p.Pro772Ser目前的信号活性类似于野生型形式。关于PROKR 2变体，先前的功能研究结果表明，p.Arg85Cys通过MAPK和Ca 2+途径适度损害受体信号传导，而p.Arg248Glu降低钙动员，但具有正常的MAPK活性。在我们的CPHD患者中存在FGFR 1和PROKR 2的功能丧失变体，表明这些罕见变体对表型具有辅助和/或修饰作用。在未受影响的亲属中存在相同的变体意味着它们不能单独引起表型。其他相关的遗传和/或环境修饰剂可能在这种情况的病因学中发挥作用。
The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p.Arg85Cys and p.Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca2 + pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition.