Hereditary retinal dystrophy exhibits a wide range of phenotypes and genetic heterogeneity, which poses challenges to the molecular and clinical diagnosis of patients. In this study, we wanted to clinically characterize and investigate the molecular etiology of the atypical form of autosomal recessive retinal dystrophy in two Spanish families of close relatives. Affected members of each family exhibit a range of clinical features, including decreased vision, photophobia, poor color vision, weakened or absent ERG response, macular atrophy, and peripheral retinal pigmentation. The genetic research included homozygous mapping and exome sequencing in the first family, while Sanger DNA sequencing in the second family conducted candidate gene screening guided by homozygotes. Our method reveals nucleotide changes in CDHR1. A homozygous missense variant (c.1720C>G, p.P574A) and a homozygous single-base transition (c.1485 + 2T> C) affect the canonical 5′splice site of intron 13 respectively . Both changes are co-isolated with the disease and are not present in unrelated control populations. So far, only five mutations in CDHR1 have been identified, all of which lead to premature stop codons, leading to meaningless decay mediated by mRNA. Our work reported two previously unidentified homozygous mutations in CDHR1, further expanding the mutation spectrum of this gene.
Inherited retinal dystrophy (IRD) includes a large number of progressive neurodegenerative diseases, which will have a functional impact on retinal physiology and eventually lead to obvious visual impairment. IRD can be widely characterized according to the order and relative severity of any photoreceptor dysfunction or loss, including pyramidal dystrophy (CD), pyramidal rod dystrophy (CRD), and retinitis pigmentosa (RP)1. When there is primary cone dysfunction (CD/CRD), the initial symptoms include early and progressive loss of central visual acuity, poor color vision and photophobia, and RP causes night blindness in patients, which is the first obvious Symptoms 2, 3, 4. Genetically speaking, IRD shows all Mendelian inheritance patterns, namely autosomal recessive inheritance (ar), autosomal dominant inheritance (ad) or X-linked (Xl). So far, it has been identified that mutations in more than 105 genes (RetNet; http://www.sph.uth.tmc.edu/retnet/) can cause many forms of hereditary retinal dystrophy. IRDs also have genetic and clinical overlapping characteristics, for example, mutations in specific genes may cause different diseases4,5.
Functionally, proteins encoded by a large number of genes related to IRD play a key role in maintaining the structure and integrity of the photoreceptor. One of them is cadherin-related family member 1 (CDHR1, OMIM * 609502, formerly PCDH21), a member of the calcium-dependent cadherin superfamily of homologous cell adhesion proteins. Structurally, these molecules are complete proteins, and their main feature is the presence of multiple (up to 34) cadherin repeats, which is the large extracellular calcium (EC) binding structure that determines the functional spectrum of a single cadherin Domain 6,7. Cadherins are evolutionarily conserved, and even minor amino acid changes have been found to affect their binding specificity with protein partners. It is worth noting that mutations in four members of the cadherin family (including CDHR1) have been identified to cause retinal dystrophy 8, 9, 10, 11.
CDHR1 consists of six cadherin repeats, one transmembrane and one intracellular domain. The protein is present in a small part of neuronal tissue, including the olfactory bulb and retina12,13. In the retina, CDHR1 seems to function at the base of the outer part of the photoreceptor, especially at the junction between the inner and outer parts, as opposed to connecting cilia [14,15]. There is a cdhr1-/- mouse model in which gene disruption causes structural damage to the cone cells and the outer segment of the rod, and undergoes photogenic cell degeneration, making CDHR1 a major candidate disease gene for human IRD.
Historically, Bolz et al.  first carried out a comprehensive screening of a large number of IRD patients with the CDHR1 gene, and identified two missense variants with uncertain pathogenic potential because they are heterozygous. There is no second pathogenic allele in all carriers. To date, further studies have shown that only a few cases of CDHR1 mutations cause arCRD or clinically relevant forms of retinopathy, sometimes called “CDHR1-related retinopathy”, which mainly but not only affects cone photoreceptor cells2,11, 17, 18, 19. Most CDHR1 mutations identified from people with different ethnic backgrounds may cause meaningless mediated mRNA decay, resulting in reduced or no protein content in affected individuals. In this work, we describe two close relatives of Hispanic families who have studied them by using exome sequencing or “classical” sequencing analysis by the Sanger method, combining homozygous mapping and candidate gene analysis. The patient also underwent a detailed clinical evaluation through retinal imaging and electroretinogram techniques. Finally, our study resulted in two previously undescribed homozygous mutations in CDHR1.
This study identified 6 members of the RP-0763 family and 4 members of the RP-0043 family from Spain (Figure 1). As a control, 165 healthy and unrelated subjects from Spain were included.
(A) The pedigree of family RP-0763. The parents are cousins. The hollow and hollow symbols represent unaffected and affected individuals, respectively. m1/m1 refers to the existence of homozygous mutation c.1720C>G in CDHR1 (NM_033100.3), and m1/+ refers to its heterozygote. The arrow indicates the proband of the family. (B) shows the Sanger DNA sequencing chromatograms around the CDHR1 variant c.1720C>G of patient II: 2 and healthy carrier individual II:1. (C) The ancestry of family RP-0043, whose parents are also cousins. m2 / m2 refers to the existence of homozygous mutation c.1485 + 2T>C in CDHR1 (NM_033100.3), and m2 / + refers to the existence of heterozygote. The arrow indicates the proband of the family. (D) Sanger DNA sequencing chromatograms around the CDHR1 variant c.1485 + 2T>C of patient II:1 and healthy parent I:1.
This study was conducted in accordance with the purpose of the Declaration of Helsinki and was approved by the Institutional Review Board of the University of Lausanne in Switzerland and the Clinical Research Ethics Committee of the Jiménez Diaz University Foundation in Spain. Written informed consent was obtained from the subjects participating in this study and donated blood for the study. By assigning each person a digital ID to anonymize everyone; by adopting international recommendations and current Spanish laws (Ley de Investigacion Biomedica 14/2007 and LOPD), the confidentiality and protection of data can be ensured.
Affected patients underwent a comprehensive eye examination, including assessment of best corrected visual acuity (BCVA), intraocular pressure, eye movement, pupil response, biomicroscope slit lamp examination, and dilated fundus examination. Color vision was checked through 28 HUE Farnsworth or Ishihara tests. According to the guidance of the International Society for Clinical Visual Electrophysiology, visual function was assessed by static visual field examination, optical coherence tomography (Cirrus, Carl Zeiss Meditek, Dublin, California) and Ganzfield electroretinography.
Follow the manufacturer’s instructions to extract genomic DNA from 1 ml of whole blood using an automatic DNA extractor (Magna Pure Compact, Roche, Basel, Switzerland).
Use high-resolution commercial SNP arrays from Affymetrix (Affymetrix, San Diego, CA, USA) (Genome Wide Human SNP array) and Illumina (Illumina, Santa Clara, CA, USA) (Omni Whole Genome Array HumanCytoSNP) for genome-wide purification Cooperation Picture-12) Used for RP-0763 and RP-0043 respectively. The array is processed according to the manufacturer’s protocol. Through the dCHIP software, the linkage disequilibrium-hidden Markov model algorithm (LD-HMM) 20 was used to conduct the whole genome and whole gene automatic mapping.
For mutation analysis, specific primers are used to PCR amplify the entire CDHR1 open reading frame (ORF), which consists of 17 exons and their exon-intron boundaries. The primer sequences have been previously described 11 and 16, except for exon 15, a unique primer pair was designed for it (forward: 5′-ACACCCATGCCTATGTGCTC-3′, reverse: 5′-TATCTCTTGGAGCTGCTGGA-3′). PCR amplification was performed under standard conditions.
Mutation screening was performed by directly performing Sanger sequencing on the ABI 3130xl genetic analyzer (PE Applied Biosystems, Foster City, USA, California) using the Big Dye terminator cycle sequencing kit. The DNA control sample based on c.1720C>G mutation was screened by AciI (New England Biolabs, Beverly, MA, USA) based on restriction endonuclease.
In addition, according to the optimized scheme, a DNA control sample with c.1485 + 2T>C in exon 13 was screened by high-resolution melting (HRM) analysis. Real-time PCR and HRM were performed once continuously on the LightCycler 480 real-time PCR system (Roche, Basel, Switzerland), and all reactions were repeated. PCR and HRM conditions can be provided upon request. The PCR products showing abnormal HRM profiles were further analyzed by direct Sanger sequencing.
Exome sequencing was performed in II: 2 of the RP-0763 family (Figure 1). Using Agilent SureSelect Human All Exon v4 kit (Angelent, Wokingham, UK), 6μg genomic DNA was used for exome capture and library construction. The library was sequenced on Illumina HiSeq 2000 (Illumina, San Diego, California) to generate 100 bp paired-end reads. Novoalign (Novocraft, Selangor, Malaysia) version 2.05 was used to compare the readings with hg19 human reference sequencing. The Genomic Analysis Toolkit (GATK) 22 is used to refine the mapping around small indels, base quality score recalibration, and mutation calls. In order to detect potential pathogens, a proprietary filtering pipeline was implemented based on a self-made Perl script, as described previously . Finally, considering the inheritance of the same genotype from a single founder of two related patients, the variants are prioritized based on their presence in the autophagic common region.
NetGene 2 Server24 and Human Splicing Finder25 were used to analyze the potential consequences of the mutation c.1485 + 2T> C on the normal splicing of its adjacent exons. In addition, to evaluate the putative pathological properties of the missense variants we reported in this study, polymorphic phenotyping v2 (Polyphen-2) 26, classification intolerance (SIFT) 27 and mutations were also used Body Taster28.
CDHR1 protein sequences from different species, including human (H. sapiens, NP_149091.1), mouse (M. musculus, NP_570948.1), cattle (B. taurus, NP_777248.1), chicken (G. gallus, NP_001001759) .1) Xenopus (X. tropilcalis, XP_002933948.2) and zebrafish (D. rerio, NP_001005402.1) were compared using CLC Genomics Workbench (CLCbio, Qiagen, Boston, USA) to check the evolutionary conservation of their substituted amino acids Sexual residue.
For the indexed case (II: 2) of the RP-0763 family (Figure 1), the initial diagnosis was made at the age of 34. Photophobia, recovery and color vision disorders are the most obvious symptoms, followed by night blindness and loss of peripheral visual field. At the last eye exam (45 years old), the best corrected visual acuity was 0.8 for the right eye (OD) and 0.7 for the left eye (OS). Found posterior cystic cataract. 28 HUE Farnsworth test showed non-specific mild abnormalities. She presented a tubular field of vision with an islet of central vision, accompanied by temporal islets at the age of 42, and was reduced to absolute Staphylococcus at the age of 45 (Supplementary Figure S1). The fundus showed pale intervertebral discs, narrow blood vessels, sparse spicular pigmentation around the midperiphery, light yellow spots in the macula and macular retinal pigment epithelial degeneration (Figure 2). The full-field ERG is not recordable, and for the multifocal (mf) ERG, the amplitude is reduced in all recordings (Figure 3). OCT showed thinning of the fovea on both sides (Figure 2). Table 1 summarizes the clinical data. The affected siblings (II: 3) were unable to undergo eye examinations.
RP-0763 Family II: Fundus photographs and optical coherence tomography (OCT) of 2 individuals.
(A) Fundus photos taken at the age of 45 (left and right eyes), showing pale optic disc and weakened retinal blood vessels. Macular involvement is accompanied by spot pigmentation (yellow spots) and circular RPE, and the fovea (bovine eye macular degeneration). (B) Fundus photographs of the periphery of the retina (left and right eyes), showing the presence of pigment changes in the form of sparse spicular pigmentation. (C) The OCT of the left and right eyes showed a reduction in the fovea.
RP-0763 Family II: Multifocal electroretinogram (mfERG) of 2 patients for the left eye (a) and right eye (b).
The initial diagnosis of the index case (II:1) of the RP-0043 family (Figure 1) was completed in the third decade of her life. Night blindness and narrow vision are the most obvious symptoms. At the age of 33, the visual field was symmetrically reduced to 10 degrees, and the visual acuity was 0.2 OD and 1 OS. The patient has suffered from amblyopia since childhood. Fundus examination revealed pale intervertebral discs, vascular stenosis, midperipheral spicule pigmentation, and a bull’s eye macular phenotype, leading to atrophy of the circular retinal pigment epithelium (RPE) and the fovea. The full-field electroretinogram is not recordable. In the multifocal electroretinogram (mfERG), the amplitude is reduced in all cases. After further eye examination (49 years old), both eyes of the patient showed light perception vision (Table 1).
For sick sibs (II: 2), the initial diagnosis was made at the age of 32. The visual field is the central dark spot, and the visual acuity is 0.12 OD and 1 OS. The refractive error is -3 balls, -1.50 cylinder OD and -2 balls OS. 28 The HUE Farnsworth test showed changes in color vision. The fundus showed a small optic papilla, an unstructured macula, and surrounding atrophy (Table 1).
The two families reported in this study are both close relatives and retinal dystrophy, separated in an autosomal recessive pattern. Based on this information, we performed a genome-wide self-zygote mapping based on SNP. Our analysis reveals that the affected siblings of the two families share several large self-coming zones (Table 2). In particular, it is preferable to include a region containing more than 300 consecutive homozygous SNPs corresponding to a genome size of 1 Mb or more on average.
In the RP-0763 family, autophagy analysis resulted in five large autophagy regions (Table 2). The third largest selfing interval includes the 5.7 Mb genomic region on chromosome 10 (hg19: 85.7-91. Mb) containing CDHR1. After evaluating the exome sequencing data of patient II:2 (family RP-0763), we identified a homozygous mutation c.1720C>G (p.P574A) in this gene.
Dideoxy DNA sequencing confirmed the existence of this variant, which was co-segregated with retinal dystrophy in the family (Figure 1). In 165 healthy control individuals, the mutation was not detected in an internal control cohort containing complete exome and/or complete genome sequencing data from 350 unrelated individuals, or any other public database, including 1,000 Genomes Project29 (Exome Variation Server (EVS, http://evs.gs.washington.edu/EVS) and the Exome Aggregation Association (ExAC, http://exac.broadinstitute.org), which contains information from Sequencing data of more than 61,000 unrelated individuals. The p.P574A homozygous change affects proline residues, which are completely conserved from fish to human (Figure 4a), located in the fifth cadherin repeat sequence (Figure 4b). In addition, c.1720C is an evolutionarily highly conserved nucleotide with a phyloP score of 5.65 (threshold, significance> 0.95). Therefore, replacing proline residues with alanine may affect the function of CDHR1. In addition, Computer analysis of p.P574A using three different online tools predicts that the mutation may be destroyed by Polyphen (score 0.998), SIFT is harmful (score 0.00), and diseases caused by mutant tests (score 0.999).
The cross-regional amino acid sequence alignment of human CDHR1 in missense variant p.P574A and the topological structure of CDHR1 protein indicate the positions of all reported mutations.
(A) Amino acid sequence alignment of human CDHR1 with orthologous proteins of mouse, dog, cow, chicken, frog and zebrafish. The 10 upstream and 10 downstream amino acids from the missense variant P574A are depicted. Residues that are identical to the human sequence in all sequences are shown in black on a white background, while different amino acids are shown in white on a gray background. The amino acid residues where missense changes are shown in bold. (B) Mutations have been reported in the topology and location of CDHR1 protein. The intracellular domain (IC) is shown as a purple line; the transmembrane domain (TM) is shown in a box with a gray background. The extracellular domain (EC) is represented by a red oval, and the junction area between the extracellular domains is a blue box. Mutations reported in previous studies are shown in black, while mutations identified in this work are shown in red.
In the RP-0043 family, autophagy analysis resulted in seven large autophagic regions (Table 2). The largest selfing interval of a genomic region containing 47 Mb (hg: 72-118.9 Mb) contains CDHR1. Several other genes known to be associated with hereditary retinal dystrophy are also in these intervals, namely LRAT under Leber congenital substantia nigra (LCA) 30 and AILP1 under LCA, juvenile RP and autosomal dominant CRD31,32. However, because the phenotypic pictures of the two affected siblings are similar to autosomal recessive retinal degeneration, similar to the phenotype profile caused by the CDHR1 mutation, we consider CDHR1 as the main disease gene candidate to be screened in this family .
Indeed, sequence analysis of the ORF and intron-exon boundary of the gene by Sanger’s method (identified initially in patient II: 2) identified a homozygous nucleotide change c.1485 + 2T> C This affects the 5′splice site of intron 13, one of the two classically conserved nucleotides, so it may have a major impact on CDHR1 splicing. In healthy parents, mutations also appear in the affected sibs in a homozygous form and appear in a heterozygous state (Figure 1). Similar to c.1720C>G, the mutation was not detected in control individuals, nor reported in the 1000 genome database or any other public database. It is worth noting that although the base substitutions are different (c.1485 + 2T> G), previously reported that the mutated nucleotide positions in Israeli Arab families are exactly the same17. Using two different web-based platforms (NetGene 2 Server and Human Splicing Finder) for computer evaluation of c.1485 + 2T>C, it can be predicted that the donor splice site will actually be abolished (Table 3).
In this study, we identified two Spanish families with close relatives who had isolated autosomal recessive retinal degeneration and had two previously unidentified mutations in CDHR1. In particular, the genetic analysis of the RP-0763 family showed that, so far, the gene is homozygous with exon 15 and the only missense mutation (c.1720C>G, p.P574A) is associated with any type of ocular pathology. related. In family RP-0043, we reported that the homozygous splice site mutation c.1485 + 2T> C affects the second completely conserved nucleotide position of the exon 13 donor splice site.
Clinically, the diagnosis of these patients is consistent with the form of CDHR1-related retinopathy. Different autosomal recessive phenotypes have been associated with mutations in the CDHR1 gene, ranging from RP to CRD2,11,17,18,19. For the RP-0763 family, although the index case (II: 2) indicated photophobia, optotype and color vision disorders were the most obvious symptoms, she maintained good visual acuity. Therefore, the patient’s phenotype seems to be more like RP than CRD, or diffuse retinal dystrophy involving both cones and rods. Overall, compared with the phenotypes described in RP-0043 and documents 2, 11, 17, 18, and 19, the severity of the phenotype of the RP-0763 family with the missense mutation p.P574A is at least in terms of BCVA Lighter.
It has been shown that CDHR1 is not only an important protein for photoreceptor homeostasis, but also an important protein for photoreceptor development. It exists in the main base of the outer part of the photoreceptor, on the developing disc. Its exact function has not been fully elucidated, but it has been shown that the role of CDHR1 is coordinated through the use of its extracellular cadherin domain [33,14]. The ablation of cdhr1 in the mouse model can cause functional consequences of the photoreceptor, which can lead to confusion in the external part and lead to degeneration and death of the photoreceptor15. To date, seven different mutations (including those reported in this study) have been identified in CDHR1 (Figure 4b) 2, 11, 17, 18, 19. Interestingly, six of them are reported to cause premature stop codons, most likely to cause nonsense-mediated decay of mRNA, resulting in no protein products or trace protein products.
In CDHR1, the p.P574A mutation is topologically located at the end of the fifth extracellular domain (EC), overlapping with the junction region connecting two adjacent cadherin ECs. Proline 574 is highly conserved throughout the species (Figure 4a), and this element indicates the importance of its evolutionary function at a specific location. It is speculated that the linker region in cadherin plays a crucial role in protein stability and structural integrity and function. They maintain the local extracellular domain structure by interacting with Ca2+, thereby enhancing the resulting EC superstructure and preventing protein instability and immature proteolysis34,35. Proline is replaced by alanine, and two residues with completely different biochemical characteristics can be considered to be destructive to the different functions of the linker region. In addition, to confirm the concept of the pathogenicity of this mutation, three different computer-based independent computer-based tools (SIFT, Polyphen, and Mutation Taster) predicted with high scores that the p.P574A missense mutation is caused by the disease. caused.
c. 1485 + 2T> C is the second splice site mutation reported in CDHR1 so far, affecting the previously reported nucleotide positions of exon 13 and intron 13 at the same boundary. However, the basic changes are different. According to computer predictions, this DNA change significantly reduces normal splicing sites, which may lead to incorrect splicing and abnormal CDHR1 mRNA production, and CDHR1 mRNA should be degraded by nonsense-mediated mRNA.
In summary, in this work, we describe the retinal pathology that separates the two families of autosomal recessive retinal dystrophy due to two previously undescribed mutations in CDHR1, one of which is described for the first time in this gene so far The pathogenic missense changes. Using our findings, we can further understand the clinical and molecular profiles of diseases caused by CDHR1.
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We want to thank everyone who participated in this research. We would also like to thank FJD-Biobank (RD09 / 0076/00101), CIBER-ER (06/07/0036), FIS (PI: 13/00226), ONCE and Fundaluce (4019-002) for their support. Raquel Perez-Carro’s work was supported by Fundacion Conchita Rabago, and Marta Corton’s work was funded by Miguel Servet of the Salud Carlos III Institute (CP/03256). This work was also funded by the Swiss National Science Foundation (Grant 310030_138346).
Nikopoulos Konstantinos, Avila-Fernandez Almudena, Rivolta Carlo and Ayuso Carmen also contributed to this work.
Jimenez Diaz (IIS-FJD, UAM), Department of Genetics, University Hospital, Madrid Health Institute, Spain
Almudena Avila-Fernandez, Marta Corton, Maria Isabel Lopez-Molina, Raquel Perez-Carro, Olga Zurita, Blanca Garcia-Sandoval and Carmen Ayuso
KN, AAF, CR, and CA wrote the manuscript; KN, AAF, CR, and CA designed the study; KN, AAF, MC, MILM, LB, RPC, SADG, OZ, BGS, and CA performed data collection. All authors analyzed the data and reviewed the manuscript.
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Nikopoulos, K., Avila-Fernandez, A., Corton, M. Wait. Two new mutations in CDHR1 were identified in near-blooded Spanish families with autosomal recessive retinal dystrophy. Sci Rep 5, 13902 (2015). https://doi.org/10.1038/srep13902
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Post time: Dec-14-2020