A novel tandem duplication of PRDM13 in a Chinese family with North Carolina macular dystrophy

Wu, Shijing; Yuan, Zhisheng; Sun, Zixi; Zhu, Tao; Wei, Xing; Zou, Xuan; Sui, Ruifang

doi:10.1007/s00417-021-05376-w

Cited by 6 publications

(8 citation statements)

References 34 publications

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“…Genetic counseling plays an important role in the diagnosis of NCMD patients. Since NCMD shares phenotypic characteristics with other macular degenerations, such as age-related macular degeneration (AMD), Stargardt’s disease, etc., the diagnosis of NCMD only based on clinical features may lead to misdiagnosis of NCMD [ 7 , 9 ]. Genetic counseling can not only assist the diagnosis of the proband, but also identify the type of NCMD and the underlying genetic cause of the disease through whole-genome sequencing, thus providing the possibility for further treatment [ 2 , 9 ].…”

Section: Discussionmentioning

confidence: 99%

“…Since NCMD shares phenotypic characteristics with other macular degenerations, such as age-related macular degeneration (AMD), Stargardt’s disease, etc., the diagnosis of NCMD only based on clinical features may lead to misdiagnosis of NCMD [ 7 , 9 ]. Genetic counseling can not only assist the diagnosis of the proband, but also identify the type of NCMD and the underlying genetic cause of the disease through whole-genome sequencing, thus providing the possibility for further treatment [ 2 , 9 ]. For example, Clustered regularly interspaced short palindromic repeats/crispr-associated protein-9 nuclease (CRISPR/Cas9) system as a frontier tool of gene-editing tools has been studied in the treatment of retinal degenerative diseases [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…There have been few reports of NCMD in an Asian population [ 8 , 9 ]. The purpose of this research is to provide a detailed description of a Chinese family with NCMD to help better understand NCMD and to explore its possible pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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The possible pathogenesis of macular caldera in patients with North Carolina macular dystrophy

Zhu

et al. 2022

BMC Ophthalmol

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Background This study provides a detailed description of a Chinese family with North Carolina macular dystrophy (NCMD) and explores its possible pathogenesis. Methods Five individuals from a three-generation family underwent general ophthalmic examination, multi-imaging examinations and visual electrophysiology examinations when possible. Genetic characterization was carried out by target region sequencing and high-throughput sequencing in affected patients. Results Despite severe fundus changes, patients had relatively good visual acuity. Genetic analysis showed that affected patients had PRDM13 gene duplication and heterozygous mutations of the ABCA4 gene. Optical coherence tomography (OCT) showed an abnormal retinal pigment epithelium (RPE) layer in patients with grade 2 lesions, while the neurosensory retina was relatively normal. In grade 3 patients, RPE and choroid atrophy were greater than that of the neurosensory retina, showing concentric atrophy. Conclusions RPE and choroidal atrophy were found to play an important role in the development of macular caldera.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The possible pathogenesis of macular caldera in patients with North Carolina macular dystrophy

Zhu

et al. 2022

BMC Ophthalmol

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“…Five are located in the MCDR1 locus, encompassing the PRDM13 gene and a shared non-coding region (~44 kb) upstream of the gene, containing several putative CREs. 22,[30][31][32][33] The three tandem duplications located in the MCDR3 locus share a ~39 kb non-coding region in a gene desert downstream of the IRX1 gene, while only one encompasses the coding region of IRX1. 22,25 Interestingly, the shared duplicated region in MCDR3 contains candidate CREs (cCREs) during retinal development as well as a UCNE of which the functions are yet unexplored.…”

Section: Introductionmentioning

confidence: 99%

“…23,31,32 In addition, five heterozygous tandem duplications have been reported in the same locus, encompassing the PRDM13 gene and a shared non-coding region (~44 kb) upstream of the gene, containing several putative CREs. 23,[33][34][35][36] The three other NCMD-associated genetic variants are heterozygous tandem duplications located in the MCDR3 locus. These share a ~39 kb non-coding region in a gene desert downstream of the IRX1 gene, while only one out of three duplications encompasses the coding region of IRX1.…”

Section: Introductionmentioning

confidence: 99%

Multi-omics profiling, in vitro and in vivo enhancer assays dissect the cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy

Sompele

Small

Cicekdal

et al. 2022

Preprint

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North Carolina macular dystrophy (NCMD) is a rare autosomal dominant disease affecting macular development. With the identification of non-coding single nucleotide variants (SNVs) near PRDM13 and duplications overlapping a DNase I hypersensitive site (DHS) near PRDM13 or IRX1 as its underlying genetic cause, we hypothesize that NCMD is a retinal enhanceropathy. Here we aim to provide insight into the cis-regulatory mechanisms of NCMD by integrating multi-omics profiling of human retina with in vitro and in vivo enhancer assays.First, we established RegRet (http://genome.ucsc.edu/s/stvdsomp/RegRet), a genome-wide multi-omics retinal database. Next, UMI-4C profiling was performed on adult human retina to fine-map chromatin interactions of cis-regulatory elements (CREs) with the PRDM13 and IRX1 promoters. Multi-omics analysis including the UMI-4C data revealed sixteen candidate CREs (cCREs), seven for the PRDM13 and nine for the IRX1 region. Subsequently, the activity of cCREs was investigated by in vitro luciferase assays and by in vivo enhancer assays in Xenopus laevis and tropicalis. Four cCREs showed in vivo eye- and brain-specific activity in Xenopus. Furthermore, we expanded the genetic architecture of NCMD with two novel non-coding SNVs (V15, V16) with a likely effect on PRDM13 regulation. Luciferase assays showed that the non-coding SNVs that are located in the two hotspot regions of PRDM13 have an effect on cCRE activity. Interestingly, cCRE4 in which V16 is located was shown to interact with the PRDM13 promoter and demonstrated in vivo activity in Xenopus. This cCRE is active at a specific developmental stage (d103) compatible with the timepoint when retinal progenitor cells of the central retina exit mitosis. Mining of single-cell (sc) transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to emerge and begin to synapse with retinal ganglion cells. This supports the hypothesis that altered PRDM13 or IRX1 expression impairs synaptic interactions between amacrine and ganglion cells during retinogenesis. Overall, this study gained insight into the cis-regulatory mechanisms of NCMD and supports that NCMD is a retinal enhanceropathy.

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Letter to the editor regarding “A novel tandem duplication of PRDM13 in a Chinese family with North Carolina macular dystrophy”

Sui

2023

Graefes Arch Clin Exp Ophthalmol

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A novel tandem duplication of PRDM13 in a Chinese family with North Carolina macular dystrophy

Cited by 6 publications

References 34 publications

The possible pathogenesis of macular caldera in patients with North Carolina macular dystrophy

The possible pathogenesis of macular caldera in patients with North Carolina macular dystrophy

Multi-omics profiling, in vitro and in vivo enhancer assays dissect the cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy

Letter to the editor regarding “A novel tandem duplication of PRDM13 in a Chinese family with North Carolina macular dystrophy”

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