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dc.contributor.authorArlt, Annabelle
dc.contributor.authorKohlschmidt, Nicolai
dc.contributor.authorHentschel, Andreas
dc.contributor.authorBartels, Enrika
dc.contributor.authorGroß, Claudia
dc.contributor.authorTöpf, Ana
dc.contributor.authorEdem, Pınar
dc.contributor.authorSzabo, Nora
dc.contributor.authorSickmann, Albert
dc.contributor.authorMeyer, Nancy
dc.contributor.authorSchara-Schmidt, Ulrike
dc.contributor.authorLau, Jarred
dc.contributor.authorLochmüller, Hanns
dc.contributor.authorHorvath, Rita
dc.contributor.authorOktay, Yavuz
dc.contributor.authorRoos, Andreas
dc.contributor.authorHiz, Semra
dc.date.accessioned2022-03-06T02:02:41Z
dc.date.available2022-03-06T02:02:41Z
dc.date.issued2022-01-31
dc.identifier.issn1750-1172
dc.identifier.otherPMC8802438
dc.identifier.other35101074
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/334701
dc.description.abstractBACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101266602
dc.sourceessn: 1750-1172
dc.subjectFocal Dermal Hypoplasia
dc.subjectGoltz Syndrome
dc.subjectLamin A/c
dc.subjectConnective Tissue Disorder
dc.subjectEr-stress
dc.subjectProtein-serine O-palmitoleoyltransferase Porcupine
dc.subjectFibroblast Proteomics
dc.titleNovel insights into PORCN mutations, associated phenotypes and pathophysiological aspects.
dc.typeArticle
dc.date.updated2022-03-06T02:02:40Z
prism.issueIdentifier1
prism.publicationNameOrphanet J Rare Dis
prism.volume17
dc.identifier.doi10.17863/CAM.82119
dcterms.dateAccepted2021-09-30
rioxxterms.versionofrecord10.1186/s13023-021-02068-w
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidRoos, Andreas [0000-0003-2050-2115]
dc.identifier.eissn1750-1172
pubs.funder-project-idWellcome Trust (109915_A_15_Z)
cam.issuedOnline2022-01-31


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International