HS6ST1 Insufficiency Causes Self-Limited Delayed Puberty in Contrast With Other GnRH Deficiency Genes.
HS6ST1 Insufficiency Causes Self-Limited Delayed Puberty in Contrast With Other GnRH Deficiency Genes.
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与其他 GnRH 缺乏基因相比，HS6ST1 不足会导致自限性青春期延迟。
DOI：
10.1210/jc.2018-00646
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发表时间：
2018-09-01
期刊：
影响因子：
--
通讯作者：
Dunkel L
中科院分区：
文献类型：
--
作者：
Howard SR;Oleari R;Poliandri A;Chantzara V;Fantin A;Ruiz-Babot G;Metherell LA;Cabrera CP;Barnes MR;Wehkalampi K;Guasti L;Ruhrberg C;Cariboni A;Dunkel L
自限性青春期延迟（DP）分离在一个常染色体显性模式，但在很大程度上是未知的遗传基础。虽然DP有时见于低促性腺激素性性腺功能减退症（HH）患者的亲属，但尚未发现已知导致HH的基因突变与家族性自限性DP的特征分离。评估已知导致HH的基因突变对自限性DP表型的贡献。我们进行了全外显子组测序的67个先证者和93个亲属从一个大的队列的家族性自限性DP，验证了致病性的基因变异体在体外，并检查了组织表达和功能的要求，在体内的小鼠同源。一个潜在的致病性基因变异分离DP被确定在1的28个已知的HH基因检查。这种致病性变异发生在一个家系的HS 6ST 1中，并在6个受影响的成员中与该性状分离，并进行杂合传播（P = 3.01 × 10−5）。生化分析表明，这种突变降低了体外磺基转移酶活性。Hs 6st 1 mRNA在围青春期野生型小鼠下丘脑表达。GnRH神经元计数在Hs 6st 1 +/−和Hs 6st 1 +/+小鼠中相似，但尽管出生后生长正常，但Hs 6st 1 +/−小鼠的阴道开放延迟。我们已经将HS 6ST 1中的有害突变与家族性自限性DP联系起来，并表明杂合Hs 6ST 1缺失导致小鼠DP。在这项研究中，观察到的导致自限性DP和HH表型的潜在致病性突变的重叠仅限于这一个基因。HS 6ST 1的破坏性突变被发现导致家族性自限性青春期延迟（DP），杂合Hs 6ST 1缺失在小鼠中产生DP。其他GnRH缺乏基因突变未见。
Self-limited delayed puberty (DP) segregates in an autosomal-dominant pattern, but the genetic basis is largely unknown. Although DP is sometimes seen in relatives of patients with hypogonadotropic hypogonadism (HH), mutations in genes known to cause HH that segregate with the trait of familial self-limited DP have not yet been identified. To assess the contribution of mutations in genes known to cause HH to the phenotype of self-limited DP. We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited DP, validated the pathogenicity of the identified gene variant in vitro, and examined the tissue expression and functional requirement of the mouse homolog in vivo. A potentially pathogenic gene variant segregating with DP was identified in 1 of 28 known HH genes examined. This pathogenic variant occurred in HS6ST1 in one pedigree and segregated with the trait in the six affected members with heterozygous transmission (P = 3.01 × 10−5). Biochemical analysis showed that this mutation reduced sulfotransferase activity in vitro. Hs6st1 mRNA was expressed in peripubertal wild-type mouse hypothalamus. GnRH neuron counts were similar in Hs6st1+/− and Hs6st1+/+ mice, but vaginal opening was delayed in Hs6st1+/− mice despite normal postnatal growth. We have linked a deleterious mutation in HS6ST1 to familial self-limited DP and show that heterozygous Hs6st1 loss causes DP in mice. In this study, the observed overlap in potentially pathogenic mutations contributing to the phenotypes of self-limited DP and HH was limited to this one gene. A damaging mutation in HS6ST1 was found to cause familial self-limited delayed puberty (DP), and heterozygous Hs6st1 loss produced DP in mice. Mutations in other GnRH deficiency genes were not seen.
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