Mutations in IMPG1 cause vitelliform macular dystrophies

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• Vitelliform macular dystrophies (VMD) are inherited retinal disorders.
• Commonly associated genes like BEST1 and PRPH2 explain some cases, but many remain genetically undefined.
• Characterized by yellow deposits in the macula, affecting juvenile (BMD) and adult (AVMD) forms.

Purpose of the Study:

• To identify the genetic cause of VMD in families with unknown mutations.
• To investigate the role of IMPG1 in both autosomal-dominant and autosomal-recessive VMD.
• To understand the functional impact of identified IMPG1 mutations on photoreceptor structure.

Main Methods:

• Gene mapping and whole-exome sequencing in a large family with autosomal-dominant VMD.
• Identification and screening of IMPG1 mutations in additional VMD patient cohorts.
• Structural modeling to assess the impact of mutations on the SPACR protein.

Main Results:

• A novel c.713T>G (p.Leu238Arg) IMPG1 mutation was identified in three families with autosomal-dominant VMD.
• IMPG1 encodes the SPACR protein, crucial for photoreceptor extracellular matrix.
• Three additional IMPG1 mutations (one splice-site, two missense) were found in autosomal-recessive VMD cases.
• The p.Leu238Arg substitution destabilizes the SEA1 domain of SPACR.

Conclusions:

• IMPG1 mutations are a significant cause of both autosomal-dominant and autosomal-recessive VMD.
• Impairment of the interphotoreceptor matrix due to IMPG1 defects is implicated in VMD pathogenesis.
• This expands the genetic landscape of VMD and highlights the importance of IMPG1.