Chen Kui, Yang Ke, Luo Su-Shan, Chen Chen, Wang Ying, Wang Yi-Xuan, Li Da-Ke, Yang Yu-Jie, Tang Yi-Lin, Liu Feng-Tao, Wang Jian, Wu Jian-Jun, Sun Yi-Min
Department & Institute of Neurology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China.
BMC Med Genet. 2017 Aug 23;18(1):91. doi: 10.1186/s12881-017-0453-0.
Perrault syndrome is a rare multisystem disorder that manifests with sensorineural hearing loss in both sexes, primary ovarian insufficiency in females and neurological features. The syndrome is heterogeneous both genetically and phenotypically.
We reported a consanguineous family (two affected sisters) with Perrault syndrome. The proband had the characteristics of Perrault syndrome: ovarian dysgenesis, bilateral hearing loss and obvious neurological signs. Target genetic sequencing and triplet repeat primed PCR (TP-PCR) plus capillary electrophoresis was conducted to detect causative mutations in the proband. The detected variant was further confirmed in the proband and tested in other family members by Sanger sequencing. Both the proband and her sister were found homozygous for the novel variant HSD17B4 c.298G > T (p.A100S) with their parents heterozygous. Detected by western blot, the protein expression of HSD17B4 mutant was much lower than that of the wild type in SH-SY5Y cells transfected by HSD17B4 wild type or mutant plasmid, which indicated the pathogenicity of the HSD17B4 mutation.
Our findings supported that HSD17B4 was one of the genes contributing to Perrault syndrome with the likely pathogenic variant c.298G > T (p.A100S). Special manifestations of cerebellar impairment were found in cases caused by HSD17B4 mutations. Besides, attention should be paid to distinguish Perrault syndrome from D-bifunctional protein deficiency and hereditary ataxia.
佩罗特综合征是一种罕见的多系统疾病，表现为男女两性的感音神经性听力损失、女性的原发性卵巢功能不全和神经学特征。该综合征在遗传和表型上均具有异质性。
我们报告了一个患有佩罗特综合征的近亲家庭（两名患病姐妹）。先证者具有佩罗特综合征的特征：卵巢发育不全、双侧听力损失和明显的神经学体征。对先证者进行了靶向基因测序以及三联体重复引物PCR（TP-PCR）加毛细管电泳，以检测致病突变。在先证者中进一步确认了检测到的变异，并通过桑格测序在其他家庭成员中进行了检测。先证者及其姐妹均被发现对于新变异HSD17B4 c.298G>T（p.A100S）为纯合子，其父母为杂合子。通过蛋白质印迹法检测，在转染了HSD17B4野生型或突变体质粒的SH-SY5Y细胞中，HSD17B4突变体的蛋白质表达远低于野生型，这表明HSD17B4突变具有致病性。
我们的研究结果支持HSD17B4是导致佩罗特综合征的基因之一，其可能的致病变异为c.298G>T（p.A100S）。在由HSD17B4突变引起的病例中发现了小脑损伤的特殊表现。此外，应注意将佩罗特综合征与D-双功能蛋白缺乏症和遗传性共济失调相区分。
