A Peculiar Autosomal Dominant Macular Dystrophy Caused by an Asparagine Deletion at Codon 169 in the Peripherin/RDS Gene

Abstract

To describe the clinical and genetic findings in a family with a peculiar autosomal dominant macular dystrophy with peripheral deposits. Methods: All family members underwent an ophthalmic examination, and their genomic DNA was screened for mutations in the human retinal degeneration slow (peripherin/RDS) and rhodopsin genes. In selected cases, fluorescein angiography and electrophysiologic testing were performed. Results: The age at onset of the disease was between the third and fourth decades of life, starting with mild visual acuity loss and periods of metamorphopsia. Clinical signs included subretinal yellowish macular deposits evolving into geographic atrophy and retinal hypopigmentation and hyperpigmentation. Electroretinography demonstrated rod dysfunction, and electro-oculograms were mildly to severely disturbed. All affected members were found to carry a 3-base pair deletion affecting codon 169 of the peripherin/RDS gene. This mutation resulted in an asparagine (Asn) deletion in the peripherin/RDS protein and was not found in 155 control individuals. Conclusion: A deletion of Asn 169 in the peripherin/ RDS protein causes a peculiar form of autosomal dominant macular dystrophy in a large family from the Netherlands. Clinical Relevance: Characterizing the phenotype and genotype in this family may, in the long term, result in a better understanding of the precise mechanism underlying this retinal degeneration.

Genotype–phenotype associations in a large PRPH2 ‐related retinopathy cohort

“…Like prior studies, the phenotype–genotype correlations in this cohort are also difficult to determine (Khani et al, 2003; van Lith‐Verhoeven et al, 2003; Meunier et al, 2011; Roosing et al, 2014; Yang et al, 2003). Shankar et al (2015) reviewed the c.828+3A>T variant and found that 97 patients of 19 different families had diagnoses of RP, macular dystrophy, and PD.…”

“…Peripherin‐2 forms oligomeric complexes with other proteins, including the rod outer segment membrane protein‐1 (ROM‐1) and leucine‐rich repeat‐containing protein‐32/glycoprotein‐A repetitions predominant expressed in rods and is critical to the proper formation of the outer segment (Boon et al, 2008; Chakraborty, Conley, Fliesler et al, 2010; Chakraborty, Conley, Stuck et al, 2010; Conley et al, 2010; Ding et al, 2004, 2005; Duncan et al, 2011; van Lith‐Verhoeven et al, 2003; Loewen & Molday, 2000; Poetsch et al, 2001; Poloschek et al, 2010; Tam et al, 2004). The ability to review phenotype–genotype associations within a single rare disorder is advantageous for understanding the phenotypic range and properly categorizing causal genetic variation.…”

“…Peripherin‐2 localizes to the rims of cone lamellae and the rod disk of the photoreceptor outer segment in the adult retina (Chakraborty, Conley, Fliesler, & Naash, 2010; Conley, Stricker, & Naash, 2010; Loewen & Molday, 2000; Poetsch, Molday, & Molday, 2001; Tam, Moritz, & Papermaster, 2004). Peripherin‐2 forms intramolecular disulfide bonds at seven highly conserved cysteine residues within the D2 loop, forming covalently bonded homomultimeric complexes (Boon et al, 2008; Conley et al, 2010; Ding, Stricker, & Naash, 2005; Duncan et al, 2011; van Lith‐Verhoeven et al, 2003; Loewen & Molday, 2000). These molecular interactions are essential to preserving structure and function of photoreceptor outer segments (Boon et al, 2008; Chakraborty, Conley, Fliesler et al, 2010; Chakraborty, Conley, Stuck, & Naash, 2010; Ding et al, 2004, 2005; Duncan et al, 2011; van Lith‐Verhoeven et al, 2003; Loewen & Molday, 2000; Tam et al, 2004).…”

Mutations in the peripherin/RDS gene are an important cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus

“…The retinal abnormalities range from minor foveal abnormalities to multifocal pattern dystrophy and even retinitis pigmentosa. This remarkable clinical heterogeneity precludes a straightforward genotype–phenotype correlation even with larger patient series 5 8 10 12 16 18 20 29 49. Obviously, modifying factors besides the specific mutation in the peripherin/RDS gene exert an important influence on the resulting phenotype.…”

Genetic factors of age-related macular degeneration

“…The rds mouse, which, in genotype, is homozygous for a null mutation in peripherin / RDS , completely fails to develop photoreceptor discs and outer segments, and exhibits down-regulation of rod opsin expression and apoptotic loss of photoreceptor cells (Kohl et al, 1998). Peripherin/RDS mutations in codons 169, 172, and 195 have been identified in autosomal dominant macular dystrophy (Downes et al, 1999;Ekstrom et al, 1998;Lith-Verhoeven et al, 2003b;Nakazawa et al, 1995;Payne et al, 1998;Wells et al, 1993;Yanagihashi et al, 2003). Recently, Khani et al (2003)reported that a RDS mutation in codon 141 is associated with an unusual AMD-like late-onset maculopathy.…”