Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects.
Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects.
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对PORCN突变、相关表型和病理生理学方面的新见解。
DOI：
10.1186/s13023-021-02068-w
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发表时间：
2022-01-31
影响因子：
3.7
通讯作者：
Hiz S
中科院分区：
文献类型：
--
作者：
Arlt A;Kohlschmidt N;Hentschel A;Bartels E;Groß C;Töpf A;Edem P;Szabo N;Sickmann A;Meyer N;Schara-Schmidt U;Lau J;Lochmüller H;Horvath R;Oktay Y;Roos A;Hiz S
Goltz综合征(GS)是一种由PORCN突变引起的由中胚层和外胚层衍生结构缺陷引起的X连锁疾病。特征包括皮肤色素沉着条纹，眼睛和骨骼畸形，乳头多生或发育不良。一般来说，GS与男性的宫内致死有关，大多数报告的男性患者都表现出嵌合体(到目前为止只有三个非嵌合体存活的男性被描述)。此外，对GS神经功能缺陷的准确描述很少见，不那么严重的表型可能不仅是由嵌合体引起的，也可能是由较少的致病突变引起的，这表明需要对这些罕见的变异进行分子遗传学和功能研究。我们报告了两个病例：一名女孩患有典型的皮肤和骨骼异常，发育迟缓，小头畸形，穹隆变薄，脑室周围胶质细胞增生症和由PORCN无义突变(C.283C >； T，p.Arg95Ter)引起的耐药癫痫。这些联合的神经学特征的存在表明中枢神经系统易损性可能是GS患者诊断的指导性症状。另一例为男孩，乳头肥大，骨骼异常，但发育迟缓，小头畸形，脑萎缩，髓鞘发育迟缓，耐药癫痫为主要特征。未发现皮肤异常。基因分型显示，一个新的PORCN错义突变(c.847G >； C，p.Asp283His)在基因组聚合数据库(GnomAD)中缺失，但在他无症状的母亲中也发现了。考虑到母亲中排除了非随机的X染色体失活，对该指数的成纤维细胞进行了PORCN蛋白丰度和分布、对额外ER应激负荷的脆弱性以及揭示蛋白质分泌变化的分析。我们的联合发现可能提示P.Asp283His变异体的不完全外显，并通过将ER功能受损和蛋白质分泌改变添加到导致GS临床表现的病理生理过程列表中，为GS的分子病因学提供新的见解。网上版载有补充材料，可在10.1186/s13023-021-02068-w查阅。
Goltz syndrome (GS) is a X-linked disorder defined by defects of mesodermal- and ectodermal-derived structures and caused by PORCN mutations. Features include striated skin-pigmentation, ocular and skeletal malformations and supernumerary or hypoplastic nipples. Generally, GS is associated with in utero lethality in males and most of the reported male patients show mosaicism (only three non-mosaic surviving males have been described so far). Also, precise descriptions of neurological deficits in GS are rare and less severe phenotypes might not only be caused by mosaicism but also by less pathogenic mutations suggesting the need of a molecular genetics and functional work-up of these rare variants. We report two cases: one girl suffering from typical skin and skeletal abnormalities, developmental delay, microcephaly, thin corpus callosum, periventricular gliosis and drug-resistant epilepsy caused by a PORCN nonsense-mutation (c.283C > T, p.Arg95Ter). Presence of these combined neurological features indicates that CNS-vulnerability might be a guiding symptom in the diagnosis of GS patients. The other patient is a boy with a supernumerary nipple and skeletal anomalies but also, developmental delay, microcephaly, cerebral atrophy with delayed myelination and drug-resistant epilepsy as predominant features. Skin abnormalities were not observed. Genotyping revealed a novel PORCN missense-mutation (c.847G > C, p.Asp283His) absent in the Genome Aggregation Database (gnomAD) but also identified in his asymptomatic mother. Given that non-random X-chromosome inactivation was excluded in the mother, fibroblasts of the index had been analyzed for PORCN protein-abundance and -distribution, vulnerability against additional ER-stress burden as well as for protein secretion revealing changes. Our combined findings may suggest incomplete penetrance for the p.Asp283His variant and provide novel insights into the molecular etiology of GS by adding impaired ER-function and altered protein secretion to the list of pathophysiological processes resulting in the clinical manifestation of GS. The online version contains supplementary material available at 10.1186/s13023-021-02068-w.
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影响因子：
4
作者：
Maas, S. M.;Lombardi, M. P.;Hennekam, Raoul C. M.
通讯作者：
Hennekam, Raoul C. M.
影响因子：
5.2
作者：
Brady, Paul D.;Van Esch, Hilde;Vermeesch, Joris R.
通讯作者：
Vermeesch, Joris R.
DOI：
10.1073/pnas.1314810111
发表时间：
2014-06-10
影响因子：
11.1
作者：
Liebermeister, Wolfram;Noor, Elad;Milo, Ron
通讯作者：
Milo, Ron
影响因子：
3.9
作者：
Bornholdt, Dorothea;Oeffner, Frank;Grzeschik, Karl-Heinz
通讯作者：
Grzeschik, Karl-Heinz
影响因子：
4.8
作者：
Asciolla, James J.;Miele, Matthew M.;Resh, Marilyn D.
通讯作者：
Resh, Marilyn D.