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Whole exome sequencing identified novel CRB1 mutations in Chinese and Indian populations with autosomal recessive retinitis pigmentosa

View Article: PubMed Central - PubMed

ABSTRACT

Retinitis pigmentosa (RP) is a leading cause of inherited blindness characterized by progressive degeneration of the retinal photoreceptor cells. This study aims to identify genetic mutations in a Chinese family RP-2236, an Indian family RP-IC-90 and 100 sporadic Indian individuals with autosomal recessive RP (arRP). Whole exome sequencing was performed on the index patients of RP-2236, RP-IC-90 and all of the 100 sporadic Indian patients. Direct Sanger sequencing was used to validate the mutations identified. Four novel mutations and one reported mutation in the crumbs homolog 1 (CRB1) gene, which has been known to cause severe retinal dystrophies, were identified. A novel homozygous splicing mutation c.2129-1G>C was found in the three patients In family RP-2236. A homozygous point mutation p.R664C was found in RP-IC-90. A novel homozygous mutation p.G1310C was identified in patient I-44, while novel compound heterozygous mutations p.N629D and p.A593T were found in patient I-7. All mutations described above were not present in the 1000 normal controls. In conclusion, we identified four novel mutations in CRB1 in a cohort of RP patients from the Chinese and Indian populations. Our data enlarges the CRB1 mutation spectrums and may provide new target loci for RP diagnose and treatment.

No MeSH data available.


Schematic representation of the crumbs homolog 1 gene structure.The red arrow indicated the mutations reported in our study. The homozygous splicing mutation c.2129-1G>C in the CRB1 gene damaged the second laminin AG-like domain which located in the exon 7; The reported mutation p.R764C located in the exon 9 and damaged the third laminin AG-like domain; The mutation of p.G1310C located in the exon 11 and affected the function of the C-type lectin domain. The compound heterozygous mutation p.N629D and p.A593T both located in the exon 6 and affected the function of the first laminin AG-like domain.
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f4: Schematic representation of the crumbs homolog 1 gene structure.The red arrow indicated the mutations reported in our study. The homozygous splicing mutation c.2129-1G>C in the CRB1 gene damaged the second laminin AG-like domain which located in the exon 7; The reported mutation p.R764C located in the exon 9 and damaged the third laminin AG-like domain; The mutation of p.G1310C located in the exon 11 and affected the function of the C-type lectin domain. The compound heterozygous mutation p.N629D and p.A593T both located in the exon 6 and affected the function of the first laminin AG-like domain.

Mentions: In the present study, our whole exome sequencing and data analysis in an arRP Chinese family revealed a novel homozygous splicing mutation c.2129-1G>C in CRB1 according to GenBank accession number NM_001193640.1. This homozygous splicing mutation results in deletion of exon 7, which encodes the second laminin AG-like domain. As previously reported, these laminin AG-like domains are conserved from flies to mammals35 and are predicted to affect protein to protein interactions, calcium binding, or protein folding. Even one amino acid change results in loss function of the laminin AG-like domain. Therefore, the splicing mutation c.2129-1G>C in CRB1 may damage the laminin AG-like domain function more severely than missense mutations. The p.R764C mutation in CRB1 was previously reported in retinitis pigmentasa 12 in the Caucasian population in 199913, our result confirmed that this mutation caused recessive retinitis pigmentosa in the Indian population. The homozygous point mutation of p.G1310C introduces a substitution of Glycine to Cystine in the exon 11 of the CRB1 protein and is predicted probably to be damaging to the protein function through the C-type lectin domain (SIFT score is 0.002 and PolyPhen2 scores close to 1.0), thus causing retinitis pigmentosa in the Indian RP patient. The compound heterozygous mutations p.N629D and p.A593T were located in exon 6 of the CRB1 gene in the Indian population and likely affect the function of the first laminin AG-like domain of CRB1 protein dramatically. Topological organization of CRB1 and the five mutations reported in our study was shown in Fig. 4. These mutations described above were absent from public databases such as 1000 genomes or Exome Variant Server, excluding them as common polymorphisms. However, the effect of these mutations on the function of CRB1 has not yet to be determined. In order to better understand RP pathogenesis, functional studied are necessary to confirm the roles of these mutations in CRB1 gene function and the underlying molecular mechanisms.


Whole exome sequencing identified novel CRB1 mutations in Chinese and Indian populations with autosomal recessive retinitis pigmentosa
Schematic representation of the crumbs homolog 1 gene structure.The red arrow indicated the mutations reported in our study. The homozygous splicing mutation c.2129-1G>C in the CRB1 gene damaged the second laminin AG-like domain which located in the exon 7; The reported mutation p.R764C located in the exon 9 and damaged the third laminin AG-like domain; The mutation of p.G1310C located in the exon 11 and affected the function of the C-type lectin domain. The compound heterozygous mutation p.N629D and p.A593T both located in the exon 6 and affected the function of the first laminin AG-like domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037368&req=5

f4: Schematic representation of the crumbs homolog 1 gene structure.The red arrow indicated the mutations reported in our study. The homozygous splicing mutation c.2129-1G>C in the CRB1 gene damaged the second laminin AG-like domain which located in the exon 7; The reported mutation p.R764C located in the exon 9 and damaged the third laminin AG-like domain; The mutation of p.G1310C located in the exon 11 and affected the function of the C-type lectin domain. The compound heterozygous mutation p.N629D and p.A593T both located in the exon 6 and affected the function of the first laminin AG-like domain.
Mentions: In the present study, our whole exome sequencing and data analysis in an arRP Chinese family revealed a novel homozygous splicing mutation c.2129-1G>C in CRB1 according to GenBank accession number NM_001193640.1. This homozygous splicing mutation results in deletion of exon 7, which encodes the second laminin AG-like domain. As previously reported, these laminin AG-like domains are conserved from flies to mammals35 and are predicted to affect protein to protein interactions, calcium binding, or protein folding. Even one amino acid change results in loss function of the laminin AG-like domain. Therefore, the splicing mutation c.2129-1G>C in CRB1 may damage the laminin AG-like domain function more severely than missense mutations. The p.R764C mutation in CRB1 was previously reported in retinitis pigmentasa 12 in the Caucasian population in 199913, our result confirmed that this mutation caused recessive retinitis pigmentosa in the Indian population. The homozygous point mutation of p.G1310C introduces a substitution of Glycine to Cystine in the exon 11 of the CRB1 protein and is predicted probably to be damaging to the protein function through the C-type lectin domain (SIFT score is 0.002 and PolyPhen2 scores close to 1.0), thus causing retinitis pigmentosa in the Indian RP patient. The compound heterozygous mutations p.N629D and p.A593T were located in exon 6 of the CRB1 gene in the Indian population and likely affect the function of the first laminin AG-like domain of CRB1 protein dramatically. Topological organization of CRB1 and the five mutations reported in our study was shown in Fig. 4. These mutations described above were absent from public databases such as 1000 genomes or Exome Variant Server, excluding them as common polymorphisms. However, the effect of these mutations on the function of CRB1 has not yet to be determined. In order to better understand RP pathogenesis, functional studied are necessary to confirm the roles of these mutations in CRB1 gene function and the underlying molecular mechanisms.

View Article: PubMed Central - PubMed

ABSTRACT

Retinitis pigmentosa (RP) is a leading cause of inherited blindness characterized by progressive degeneration of the retinal photoreceptor cells. This study aims to identify genetic mutations in a Chinese family RP-2236, an Indian family RP-IC-90 and 100 sporadic Indian individuals with autosomal recessive RP (arRP). Whole exome sequencing was performed on the index patients of RP-2236, RP-IC-90 and all of the 100 sporadic Indian patients. Direct Sanger sequencing was used to validate the mutations identified. Four novel mutations and one reported mutation in the crumbs homolog 1 (CRB1) gene, which has been known to cause severe retinal dystrophies, were identified. A novel homozygous splicing mutation c.2129-1G>C was found in the three patients In family RP-2236. A homozygous point mutation p.R664C was found in RP-IC-90. A novel homozygous mutation p.G1310C was identified in patient I-44, while novel compound heterozygous mutations p.N629D and p.A593T were found in patient I-7. All mutations described above were not present in the 1000 normal controls. In conclusion, we identified four novel mutations in CRB1 in a cohort of RP patients from the Chinese and Indian populations. Our data enlarges the CRB1 mutation spectrums and may provide new target loci for RP diagnose and treatment.

No MeSH data available.