Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of Hyperphosphatasia with Mental...

Area of Science:

• Genetics
• Biochemistry
• Molecular Biology

Background:

• Mabry syndrome (HPMRS) is a heterogeneous disorder caused by defects in glycosylphosphatidylinositol (GPI) anchor synthesis or maturation.
• Clinical manifestations of HPMRS range from severe syndromic forms to mild intellectual disability.
• Pathogenic mutations in genes like PGAP3 are found in about half of HPMRS patients, often within coding regions.

Purpose of the Study:

• To develop and validate a screening approach for detecting functionally relevant mutations in GPI pathway genes.
• To improve the diagnostic yield for HPMRS, particularly in cases with intellectual disability and elevated serum alkaline phosphatase.
• To identify novel pathogenic mutations, including noncoding variants, in genes involved in GPI anchor synthesis.

Main Methods:

• Development of a screening approach using sequence-specific baits for GPI pathway gene transcripts.
• Application of the screening method to detect mutations in coding and noncoding regions (introns, 5' and 3' UTRs).
• Analysis of mutations in eight affected individuals from diverse ethnic backgrounds.

Main Results:

• Identification of seven novel pathogenic mutations in the PGAP3 gene in eight affected individuals.
• Discovery of five missense mutations, one intronic mutation (c.558-10G>A) causing aberrant splicing, and one 3' UTR mutation (c.*559C>T) affecting mRNA levels.
• Demonstration that the novel screening approach effectively detects alterations in key GPI pathway genes.

Conclusions:

• The developed screening approach is a valuable tool for rapid detection of mutations in GPI pathway genes.
• Identifying noncoding mutations significantly increases the diagnostic rate for HPMRS.
• This method enhances the genetic diagnosis of HPMRS, aiding in understanding its heterogeneity.