Mutations in IMPG1 Cause Vitelliform Macular Dystrophies

Abstract

Vitelliform macular dystrophies (VMD) are inherited retinal dystrophies characterized by yellow, round deposits visible upon fundus examination and encountered in individuals with juvenile Best macular dystrophy (BMD) or adult-onset vitelliform macular dystrophy (AVMD). Although many BMD and some AVMD cases harbor mutations in BEST1 or PRPH2, the underlying genetic cause remains unknown for many affected individuals. In a large family with autosomal-dominant VMD, gene mapping and whole-exome sequencing led to the identification of a c.713T>G (p.Leu238Arg) IMPG1 mutation, which was subsequently found in two other families with autosomal-dominant VMD and the same phenotype. IMPG1 encodes the SPACR protein, a component of the rod and cone photoreceptor extracellular matrix domains. Structural modeling indicates that the p.Leu238Arg substitution destabilizes the conserved SEA1 domain of SPACR. Screening of 144 probands who had various forms of macular dystrophy revealed three other IMPG1 mutations. Two individuals from one family affected by autosomal-recessive VMD were homozygous for the splice-site mutation c.807+1G>T, and two from another family were compound heterozygous for the mutations c.461T>C (p.Leu154Pro) and c.1519C>T (p.Arg507(∗)). Most cases had a normal or moderately decreased electrooculogram Arden ratio. We conclude that IMPG1 mutations cause both autosomal-dominant and -recessive forms of VMD, thus indicating that impairment of the interphotoreceptor matrix might be a general cause of VMD.

Mutation analysis ofBEST1in Japanese patients with Best's vitelliform macular dystrophy

“…Recently, two new causal genes ( IMPG1 and IMPG2 ) have been identified in 13 patients (four families) with adult-onset vitelliform macular dystrophy in which EOG is normal or only slightly reduced 30 31. The two secreted proteins (IMPG1 and IMPG2), components of the inter photo receptor matrix, are synthesised by the photo receptors and located in the subretinal space.…”

Retinal structure in young patients aged 10 years or less with Best vitelliform macular dystrophy

“…Recently it has been shown that mutations in the IMPG (interphotoreceptor matrix proteoglycan 1) genes (IMPG1 and IMPG2) may cause macular dystrophy, 6 with vitelliform material located above the retinal pigment epithelium, and with preservation of this epithelium by SD-OCT [22,23]. However onset occurred later than in Best disease, after 30 years of age [22,23].…”

Differentiating drusen: Drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes

“…SPACR is highly homologous to SPACRCAN (sialoprotein associated with photoreceptor cone and rod proteoglycans), a 200 kDa protein encoded by IMPG2 (interphotoreceptor matrix proteoglycan 2) and also found in the interphotoreceptor matrix (Acharya et al, 2000). Mutations in IMPG1 have been associated with both dominant and recessive forms of atypical vitelliform macular dystrophy (VMD) (Manes et al, 2013). In one family carriers of heterozygous mutations that result in recessive VMD showed an early onset drusen phenotype (family NA186) (Manes et al, 2013).…”

“…Mutations in IMPG1 have been associated with both dominant and recessive forms of atypical vitelliform macular dystrophy (VMD) (Manes et al, 2013). In one family carriers of heterozygous mutations that result in recessive VMD showed an early onset drusen phenotype (family NA186) (Manes et al, 2013). Heterozygous IMPG2 mutations have also been reported to cause atypical vitelliform macular dystrophy whilst bi-allelic mutations cause RP, often with early macular involvement (Bandah-Rozenfeld et al, 2010).…”