A novel duplication of PRMD13 causes North Carolina macular dystrophy: overexpression of PRDM13 orthologue in drosophila eye reproduces the human phenotype

Abstract

In this study, we report a novel duplication causing North Carolina macular dystrophy (NCMD) identified applying whole genome sequencing performed on eight affected members of two presumed unrelated families mapping to the MCDR1 locus. In our families, the NCMD phenotype was associated with a 98.4 kb tandem duplication encompassing the entire CCNC and PRDM13 genes and a common DNase 1 hypersensitivity site. To study the impact of PRDM13 or CCNC dysregulation, we used the Drosophila eye development as a model. Knock-down and overexpression of CycC and CG13296, Drosophila orthologues of CCNC and PRDM13, respectively, were induced separately during eye development. In flies, eye development was not affected, while knocking down either CycC or CG13296 mutant models. Overexpression of CycC also had no effect. Strikingly, overexpression of CG13296 in Drosophila leads to a severe loss of the imaginal eye-antennal disc. This study demonstrated for the first time in an animal model that overexpression of PRDM13 alone causes a severe abnormal retinal development. It is noteworthy that mutations associated with this autosomal dominant foveal developmental disorder are frequently duplications always including an entire copy of PRDM13, or variants in one DNase 1 hypersensitivity site at this locus.

Unique noncoding variants upstream of PRDM13 are associated with a spectrum of developmental retinal dystrophies including progressive bifocal chorioretinal atrophy

“…Two vertical bars highlighted in grey indicate the variants identified in Family 1–3 (GRCh37/hg19 chr6:100,046,804T in Family 1 and 2; chr6:100,046,783A in Family 3) 7.8 Kb from the PRDM13 transcription start site and 5.7 Kb downstream of the three noncoding single‐nucleotide variants (V1‐V3; Small et al, ; chr6:100,040,906, chr6:100,040,987, and chr6:100,041,040, respectively). V4, V6, and V7 denote previously identified tandem duplications that overlap V1‐V3 SNVs and the genes CCNC and PRDM13 (Bowne et al, ; Manes et al, ; Small et al, ). V5 is not depicted on this schematic because it is located at the MCDR3 locus (chr5q; Small et al, ).…”

“…Given the phenotypic similarity observed in Family 3 to both NCMD and PBCRA, it was hypothesised that the disease‐associated genetic variant may be located within the associated loci. Using the WGS SNV and structural variant (SV) call data and manual interrogation of the paired‐end reads using the Integrative Genomics Viewer (IGV; Thorvaldsdóttir, Robinson, & Mesirov, ),) all known NCMD‐associated variants were excluded at both the chr5 and chr6 loci (Bowne et al, ; Cipriani, Silva et al, ; Manes et al, ; Small et al, ). At the PBCRA/MCDR1 locus, 75 SNV variants with MAF < 0.01 (and allele count <3 from NIHR data set), were shared, of which 18 were absent from gnomAD (Table S3).…”

“…The spectrum of variants associated with disease at this locus suggests that rather than loss of function, the PRDM13 expression may be spaciotemporally dysregulated. Overexpression models suggest that PRDM13 has a toxic effect on photoreceptors in prenatal mice with no perturbation of amacrine cell lineages (Goodson et al, ); it was also shown to impair eye development in Drosophila and Xenopus (Bessodes, Parain, Bronchain, Bellefroid, & Perron, ; Manes et al, ). Conversely, murine knockout of Prdm13 results only in alteration of amacrine cell development without functional vision loss (Watanabe et al, ).…”

“…Recently, the likely variants underlying NCMD at the MCDR1 locus have been elucidated: three novel noncoding SNVs located in a predicted DNase1 hypersensitivity site (DHS), in an intergenic region upstream of PRDM13, TSTD3, and CCNC were identified in 12 NCMD families (Small et al, ). In addition, three distinct tandem duplications encompassing PRDM13 and its upstream region were also reported (Bowne et al, ; Manes et al, ; Small et al, ). Tandem duplications were also identified on a second locus at 5p21 (MCDR3, MIM# 608850), where the critical region for phenotype was narrowed down to a 39 kb noncoding region (Cipriani, Silva et al, ; Small et al, ).…”

Peptidomic analysis reveals multiple protection of human breast milk on infants during different stages

“…HNRNPK was related to lung development (Yang et al, 2013), PRDM13 was related to eyes development and lipid metabolism (Manes et al, 2017;Satoh, Brace, Rensing, & Imai, 2015). In mature milk, we found 18 peptides derived from 12 proteins were both located in domains and predicted to be related to neonatal immunity, energy metabolism, and tissues and organs development.…”