An intronic haplotype in α galactosidase A is associated with reduced mRNA expression in males with cryptogenic...

Area of Science:

• Genetics
• Neurology
• Biochemistry

Background:

• Fabry disease, an X-linked lysosomal disorder, is screened in patients with unexplained early-onset stroke.
• Fabry patients with stroke often exhibit severe cardiac and renal complications, benefiting from early diagnosis and enzyme replacement therapy (ERT).

Purpose of the Study:

• To investigate the association between Fabry disease (alpha-galactosidase A gene [GLA]) intronic variants and cryptogenic stroke in an Israeli cohort.
• To determine if identified GLA intronic variants contribute to reduced enzyme activity or disease pathology.

Main Methods:

• Sequencing of the GLA gene in 175 Israeli patients with unexplained cryptogenic stroke.
• Analysis of identified intronic variants, including segregation within families.
• Assessment of enzyme activity and mRNA expression in affected males.
• Evaluation of splice-site defects and X-chromosome inactivation in females.

Main Results:

• Six patients with 2-4 GLA intronic variants were identified; some variants were familial.
• Two specific intronic variants (c.640-16A>G and c.1000-22C>T) were common.
• Three males with a common four-variant intronic haplotype exhibited low residual enzyme activity and reduced mRNA expression (~50%).
• No splice-site defects or highly skewed X-chromosome inactivation were found.

Conclusions:

• GLA intronic variants alone do not appear to be pathogenic.
• A specific intronic haplotype in males with cryptogenic stroke is associated with reduced alpha-galactosidase A expression and function.
• This association may contribute to the pathophysiology of cryptogenic stroke in a subset of patients.