Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, Avenida Doutor Eneas de Carvalho Aguiar 155, 2° Andar, Bloco 6, CEP 05403-900 São Paulo, São Paulo, Brazil.
Eur J Endocrinol. 2011 Jul;165(1):145-50. doi: 10.1530/EJE-11-0199. Epub 2011 May 4.
Necdin activates GNRH gene expression and is fundamental for the development, migration, and axonal extension of murine GNRH neurons. In humans, necdin plays a potential role in the hypogonadotropic hypogonadism phenotype in patients with Prader-Willi syndrome.
To investigate necdin gene (NDN) variants in patients with isolated hypogonadotropic hypogonadism (IHH).
We studied 160 Brazilian patients with IHH, which includes 92 with Kallmann syndrome and 68 with normosmic IHH. Genomic DNA was extracted and the single NDN exon was amplified and sequenced. To measure GNRH transcriptional activity, luciferase reporter plasmids containing GNRH regulatory regions were transiently transfected into GT1-7 cells in the presence and absence of overexpressed wild-type or mutant necdin.
A heterozygous variant of necdin, p.V318A, was identified in a 23-year-old male with Kallmann syndrome. The p.V318A was also present in affected aunt and his father and was absent in 100 Brazilian control subjects. Previous FGFR1 gene analysis revealed a missense mutation (p.P366L) in this family. Functional studies revealed a minor difference in the activation of GNRH transcription by mutant protein compared with wild type in that a significant impairment of the necdin protein activity threshold was observed.
A rare variant of necdin (p.V318A) was described in a family with Kallmann syndrome associated with a FGFR1 mutation. Familial segregation and in vitro analysis suggested that this non-synonymous variant did not have a direct causative role in the hypogonadism phenotype. NDN mutations are not a frequent cause of congenital IHH.
Necdin 激活 GnRH 基因表达，对鼠 GnRH 神经元的发育、迁移和轴突延伸至关重要。在人类中，Necdin 在 Prader-Willi 综合征患者的促性腺激素低下性性腺功能减退症表型中发挥潜在作用。
研究孤立性促性腺激素低下性性腺功能减退症（IHH）患者的 Necdin 基因（NDN）变异。
我们研究了 160 名巴西 IHH 患者，其中包括 92 名 Kallmann 综合征患者和 68 名正常嗅觉 IHH 患者。提取基因组 DNA，扩增并测序单个 NDN 外显子。为了测量 GnRH 转录活性，将含有 GnRH 调节区的荧光素酶报告质粒瞬时转染到 GT1-7 细胞中，在存在和不存在过表达野生型或突变型 Necdin 的情况下。
在一名 23 岁的 Kallmann 综合征男性中发现了 Necdin 的杂合变异体 p.V318A。该 p.V318A 也存在于受影响的阿姨和他的父亲中，而在 100 名巴西对照中不存在。先前的 FGFR1 基因分析显示该家族存在错义突变（p.P366L）。功能研究显示，突变蛋白对 GnRH 转录的激活与野生型略有不同，因为观察到 Necdin 蛋白活性阈值的显著损伤。
在一个与 FGFR1 突变相关的 Kallmann 综合征家族中描述了 Necdin（p.V318A）的罕见变异。家族分离和体外分析表明，这种非同义变异体在性腺功能减退症表型中没有直接的因果作用。NDN 突变不是先天性 IHH 的常见原因。
