Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Goltz syndrome (GS) is an X-linked disorder characterized by defects in mesodermal and ectodermal structures, caused by PORCN mutations.
• GS typically presents with skin pigmentation anomalies, ocular and skeletal malformations, and nipple abnormalities.
• Male lethality in utero is common, with most surviving males exhibiting mosaicism; neurological deficits are rarely detailed.

Observation:

• Two cases are presented: a girl with typical GS features plus significant neurological deficits (developmental delay, microcephaly, epilepsy) due to a PORCN nonsense mutation.
• A boy with milder GS features (nipple and skeletal anomalies) but prominent neurological issues (developmental delay, microcephaly, epilepsy) had a novel PORCN missense mutation.
• The boy's asymptomatic mother carried the same missense mutation, suggesting incomplete penetrance.

Findings:

• Neurological symptoms, including developmental delay, microcephaly, and drug-resistant epilepsy, can be prominent in Goltz syndrome.
• A novel PORCN missense mutation (c.847G>C, p.Asp283His) was identified in a male patient and his asymptomatic mother, indicating potential incomplete penetrance.
• Functional analysis of the patient's fibroblasts revealed impaired endoplasmic reticulum (ER) function and altered protein secretion.

Implications:

• Neurological manifestations should be considered key diagnostic indicators for Goltz syndrome.
• The findings expand the understanding of GS pathophysiology, implicating ER dysfunction and disrupted protein secretion.
• This research underscores the importance of molecular genetics and functional studies for rare variants of GS.