PMM2 intronic branch-site mutations in CDG-Ia

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Congenital Disorders of Glycosylation (CDG, OMIM#212065)-Ia is a severe autosomal recessive disorder.
• It is characterized by central nervous system dysfunction and multiorgan failure.
• These clinical manifestations are linked to mutations in the PMM2 gene.

Observation:

• Two patients with CDG-Ia were identified as compound heterozygotes.
• They carried two novel intronic mutations: c.340 -23A > G (IVS7 -23A > G) in intron 7 and c.179 -25A > G (IVS2 -25A > G) in intron 2.
• These mutations affect a conserved adenosine in a consensus branch-site sequence and are associated with missense mutations (R141H and D65Y).

Findings:

• The intronic mutations c.179 -25A > G and c.340 -23A > G lead to the loss of exon 3 and exon 8 from the RNA transcript, respectively.
• This exon skipping is a direct consequence of the intronic sequence alterations.
• The identified mutations provide new insights into the molecular mechanisms underlying CDG-Ia.

Implications:

• These intronic mutations can complicate molecular diagnosis of CDG-Ia.
• Failure to use appropriate intronic primers can lead to missed diagnoses.
• Comprehensive molecular diagnostic strategies must include both DNA and mRNA analysis to accurately identify all PMM2 gene mutations causing CDG-Ia.