Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects

Orphanet Journal of Rare Diseases

Jarred Lau¹  Hanns Lochmüller²  Nora Szabo³  Rita Horvath³  Andreas Roos⁴  Pınar Edem⁵  Annabelle Arlt⁶  Nicolai Kohlschmidt⁶  Enrika Bartels⁶  Claudia Groß⁶  Semra Hiz⁷  Yavuz Oktay⁸  Ana Töpf⁹  Albert Sickmann^1,10  Andreas Hentschel^1,10  Ulrike Schara-Schmidt^1,11  Nancy Meyer^1,11 

[1] Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada;Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada;Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada;Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada;Centro Nacional de Análisis Genómico (CNAG-CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Catalonia, Spain;Department of Clinical Neurosciences, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK;Department of Clinical Neurosciences, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK;Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada;Department of Medical Biology, School of Medicine, Dokuz Eylul University, Izmir, Turkey;Institute of Clinical Genetics and Tumor Genetics, Bonn, Germany;Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey;Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey;Department of Medical Biology, School of Medicine, Dokuz Eylul University, Izmir, Turkey;Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey;John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK;Leibniz Institute for Analytical Sciences (ISAS), Dortmund, Germany;Pediatric Neurology, Faculty of Medicine, University of Duisburg-Essen, University Hospital, Essen, Germany;

关键词: Goltz syndrome;    Focal dermal hypoplasia;    Protein-serine O-palmitoleoyltransferase porcupine;    Fibroblast proteomics;    Lamin a/c;    Connective tissue disorder;    ER-stress;   

DOI  :  10.1186/s13023-021-02068-w

来源: Springer

【 摘 要 】

BackgroundGoltz 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.ResultsWe 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.ConclusionsOur 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.

【 授权许可】

CC BY