Discovery and functional analysis of a novel ALPK1 variant in ROSAH syndrome

Area of Science:

• Genetics
• Molecular Biology
• Ophthalmology

Background:

• ROSAH syndrome is an autosomal dominant disorder linked to ALPK1 gene variants.
• Previous known variants include Thr237Met and Tyr254Cys in ALPK1.
• The syndrome presents with ocular inflammation, optic nerve edema, retinal degeneration, and potential blindness.

Purpose of the Study:

• Identify the genetic cause of ROSAH syndrome in a new family.
• Characterize the functional consequences of a novel ALPK1 variant.
• Explore therapeutic strategies for ROSAH syndrome.

Main Methods:

• Genetic sequencing to identify variants in affected individuals.
• Protein activity assays using bacterial and human metabolites.
• Structural analysis of ALPK1 variants.

Main Results:

• A novel ALPK1 variant, Ser277Phe, was identified as causative for ROSAH syndrome.
• ALPK1[Ser277Phe] exhibits altered substrate specificity, activated by UDP-mannose and ADP-ribose.
• This variant shows constitutive activity, explaining disease pathogenesis.
• Mutational analysis revealed the Ser277Phe substitution alters specificity independent of the Ser277-Tyr254 hydrogen bond.

Conclusions:

• The novel ALPK1 Ser277Phe variant causes ROSAH syndrome with severe ocular manifestations.
• Altered ALPK1 activity by this variant provides a molecular basis for the disease.
• Understanding these variants opens avenues for developing targeted inhibitory drugs.