Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex

Area of Science:

• Genetics
• Molecular Biology
• Dermatology

Background:

• Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in TSC1 or TSC2 genes.
• The TSC1/TSC2 gene products form a complex regulating the mammalian target of rapamycin complex 1 (mTORC1) pathway.
• TSC typically presents with neurological, dermatological, and visceral manifestations.

Purpose of the Study:

• To investigate the molecular basis of a TSC family with atypical presentation, specifically lacking renal manifestations.
• To determine the pathogenicity of a "silent" substitution in the TSC2 gene.
• To explore the role of mTORC1 signaling in TSC-associated hypopigmented macules.

Main Methods:

• Family-based genetic analysis to identify the causative mutation.
• Splicing assays to analyze the effect of the TSC2 variant.
• Cellular studies using patient-derived fibroblasts to assess mTORC1 signaling.
• Comparison of mTORC1 activity in fibroblasts from lesional and non-lesional skin.

Main Results:

• A novel "silent" substitution (c.4149C>T, p.Ser1383Ser) in TSC2 was identified in affected family members.
• This substitution creates an alternative splice site, leading to truncated, non-functional TSC2 transcripts.
• Hypopigmented macules in patients exhibited constitutive mTORC1 activation, while non-lesional skin showed partial mTORC1 deregulation.

Conclusions:

• The "silent" TSC2 variant c.4149C>T is pathogenic, causing alternative splicing and contributing to a milder TSC phenotype.
• Constitutive mTORC1 activation in skin is associated with the development of hypopigmented macules in TSC.
• This study highlights the importance of evaluating "silent" variants and the role of mTORC1 in TSC pathogenesis.