Twenty-five novel mutations including duplications in the ATP7A gene

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Menkes disease (MD) and occipital horn syndrome (OHS) are X-linked disorders caused by ATP7A gene mutations, leading to copper deficiency.
• MD presents severe neurological issues, while OHS involves connective tissue abnormalities.
• Previous studies identified deletions and point mutations in ATP7A.

Purpose of the Study:

• To identify novel mutations in the ATP7A gene in patients with MD or OHS.
• To expand the understanding of the mutation spectrum associated with these allelic disorders.
• To investigate the frequency and types of ATP7A alterations in a cohort of patients.

Main Methods:

• Molecular analysis of the ATP7A gene in 40 patients with suspected MD or OHS.
• Identification and characterization of point mutations (missense, splice site, nonsense, insertions/deletions) and large rearrangements (deletions, duplications).

Main Results:

• Identified 25 novel mutations in the ATP7A gene, including 23 point mutations and 7 intragenic deletions.
• Discovered four whole exon duplications, broadening the known mutation types.
• ATP7A alterations were detected in 85% of patients, with two-thirds being point mutations and one-third large rearrangements.
• 66.6% of point mutations impaired ATP7A transcript splicing, a higher frequency than anticipated.

Conclusions:

• The study expands the spectrum of ATP7A mutations associated with MD and OHS, including novel point mutations and duplications.
• Impaired ATP7A transcript splicing is a frequent consequence of point mutations in these disorders.
• The findings confirm the pathogenic role of ATP7A mutations, especially missense and splice site variants, in copper deficiency disorders.