C19orf12 gene variants causing mitochondrial membrane protein-associated neurodegeneration (MPAN)

Area of Science:

• Neurogenetics
• Neurodegenerative Diseases
• Molecular Genetics

Background:

• Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare, inherited neurodegenerative disorder.
• MPAN is caused by variants in the C19orf12 gene, leading to spastic paraplegia, parkinsonism, and cognitive/behavioral symptoms.
• Understanding the clinical and genetic spectrum of MPAN is crucial for diagnosis and management.

Purpose of the Study:

• To present detailed clinical, radiological, and genetic findings of seven MPAN patients from six families.
• To characterize the phenotypic variability based on age of onset.
• To identify and analyze novel and known C19orf12 variants and their functional consequences.

Main Methods:

• Clinical and neurological examinations.
• Brain magnetic resonance imaging (MRI) for radiological assessment.
• Whole-exome sequencing for genetic variant identification.
• RT-PCR and Sanger sequencing for transcript analysis of splice-site variants.

Main Results:

• Seven patients exhibited diverse phenotypes: childhood-onset with spastic ataxia and optic atrophy; adult-onset with cognitive, behavioral, and parkinsonian symptoms.
• MRI revealed characteristic mineralization (pallidal splitting sign) and cerebellar atrophy in some patients.
• Exome sequencing identified six C19orf12 variants, including two novel splice-site and four known missense variants.
• Transcript analysis confirmed a splice defect and the use of an alternative cryptic splice site for the c.194-2delA variant.

Conclusions:

• The study expands the clinical and genetic spectrum of MPAN, correlating C19orf12 variants with distinct phenotypes.
• Genetic testing is vital for diagnosing MPAN and understanding the impact of C19orf12 variants.
• Functional analysis of splice-site variants provides insights into MPAN pathogenesis.