Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects.
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Authors
Arlt, Annabelle
Kohlschmidt, Nicolai
Hentschel, Andreas
Bartels, Enrika
Groß, Claudia
Töpf, Ana
Edem, Pınar
Szabo, Nora
Sickmann, Albert
Meyer, Nancy
Schara-Schmidt, Ulrike
Lau, Jarred
Lochmüller, Hanns
Horvath, Rita
Oktay, Yavuz
Hiz, Semra
Publication Date
2022-01-31Journal Title
Orphanet J Rare Dis
ISSN
1750-1172
Publisher
Springer Science and Business Media LLC
Volume
17
Issue
1
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Arlt, A., Kohlschmidt, N., Hentschel, A., Bartels, E., Groß, C., Töpf, A., Edem, P., et al. (2022). Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects.. Orphanet J Rare Dis, 17 (1) https://doi.org/10.1186/s13023-021-02068-w
Abstract
BACKGROUND: 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.
Keywords
Focal Dermal Hypoplasia, Goltz Syndrome, Lamin A/c, Connective Tissue Disorder, Er-stress, Protein-serine O-palmitoleoyltransferase Porcupine, Fibroblast Proteomics
Sponsorship
Wellcome Trust (109915_A_15_Z)
Identifiers
PMC8802438, 35101074
External DOI: https://doi.org/10.1186/s13023-021-02068-w
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334701
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