A silent nucleotide substitution in the ATP7A gene in a child with Menkes disease

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Menkes disease (MD) is a rare X-linked neurodegenerative disorder.
• It is typically caused by mutations in the ATP7A gene, affecting copper transport.
• Classical MD presents with severe neurological impairment and connective tissue abnormalities.

Purpose of the Study:

• To report a novel synonymous ATP7A gene substitution causing classical Menkes disease.
• To investigate the molecular mechanism by which this substitution leads to MD.
• To expand the understanding of genotype-phenotype correlations in Menkes disease.

Main Methods:

• Genetic sequencing of the ATP7A gene in a patient with classical MD.
• Analysis of mRNA splicing patterns using RT-PCR.
• In silico prediction of splicing effects.

Main Results:

• A novel synonymous substitution, c.2781G>A (p.K927K), was identified in the ATP7A gene.
• This substitution, located at the last nucleotide of exon 13, disrupted normal mRNA splicing.
• Aberrant transcripts lacking exon 13, or exons 11-13, were detected, with minimal normal transcript levels.
• This is the first reported case of a synonymous ATP7A substitution causing Menkes disease.

Conclusions:

• Synonymous ATP7A gene substitutions can act as causative mutations for classical Menkes disease.
• Disruption of mRNA splicing is a key mechanism leading to MD in this case.
• This finding broadens the spectrum of mutations associated with Menkes disease and emphasizes the importance of evaluating splicing effects for synonymous variants.