Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects

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.

A Homozygous PPP1R21 Splice Variant Associated with Severe Developmental Delay, Absence of Speech, and Muscle Weakness Leads to Activated Proteasome Function

“…Immunoblot studies on whole proteins extracts of the PPP1R21-patient and two pooled controls were carried out as described previously [ 15 ] utilizing the primary antibodies listed in supplementary Table 2 .…”

Prenatal diagnosis of PORCN‐related developmental syndrome in a fetus: A novel phenotype

“…3 Developmental abnormalities of the eye (include a spectrum of anomalies of the lacrimal glands, iris and retina) are often associated with craniofacial findings, and skeletal abnormalities include limb malformation syndactyly and/or ectrodactyly. 4 Psychomotor development is usually normal. 2,4,5 All these anomalies show a segmental arrangement reflecting functional X-chromosome mosaicism.…”

“…Skin manifestations present at birth include hypoplastic areas of skin and the syndrome is also known as FDH 3 . Developmental abnormalities of the eye (include a spectrum of anomalies of the lacrimal glands, iris and retina) are often associated with craniofacial findings, and skeletal abnormalities include limb malformation syndactyly and/or ectrodactyly 4 . Psychomotor development is usually normal 2,4,5 .…”

“…4 Psychomotor development is usually normal. 2,4,5 All these anomalies show a segmental arrangement reflecting functional X-chromosome mosaicism. 6 This case study emphasizes differing and overlapping phenotypes between prenatal and postnatal diagnosis, complicating pathogenic variant interpretation.…”

PORCN‐related microphthalmia with limb anomalies: Case report and literature review

“…Although germline-derived pathogenic variants in PORCN (porcupine O-acyltransferase) on Xp11.23 are known to cause focal dermal hypoplasia (FDH) (alias, Goltz-Gorlin syndrome) (OMIM #305600) recognized as an apparently X-linked dominant male-lethal disorder (Bostwick et al, 2016), recent studies have revealed that several germline-derived PORCN variants lead to an apparently X-linked recessive disorder, with an abnormal phenotype in hemizygous males and a normal phenotype in heterozygous females (Arlt et al, 2022;Brady et al, 2015;Madan et al, 2017;Wawrocka et al, 2021).…”