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A new mutation in the RP1L1 gene in a patient with occult macular dystrophy associated with a depolarizing pattern of focal macular electroretinograms.

Kabuto T, Takahashi H, Goto-Fukuura Y, Igarashi T, Akahori M, Kameya S, Iwata T, Mizota A, Yamaki K, Miyake Y, Takahashi H - Mol. Vis. (2012)

Bottom Line: The variant c.3596 C>G in exon 4 resulted in the substitution of cysteine for serine at amino acid position 1199.The serine at position 1199 is well conserved among the RP1L1 family in other species.We have demonstrated in a Japanese patient the possibility that sporadic OMD may also be caused by an RP1L1 mutation.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan.

ABSTRACT

Purpose: To determine whether a mutation in the RP1-like protein 1 (RP1L1) gene is present in a Japanese patient with sporadic occult macular dystrophy (OMD) and to examine the characteristics of focal macular electroretinograms (ERGs) of the patient with genetically identified OMD.

Methods: An individual with OMD underwent detailed ophthalmic clinical evaluations including focal macular ERGs. Mutation screening of all coding regions and flanking intron sequences of the RP1L1 gene were performed with DNA sequencing analysis in this case with OMD.

Results: A new RP1L1 mutation (c.3596 C>G in exon 4) was identified. The variant c.3596 C>G in exon 4 resulted in the substitution of cysteine for serine at amino acid position 1199. The serine at position 1199 is well conserved among the RP1L1 family in other species. Four out of five computational assessment tools predicted that this mutation is damaging to the protein function. This mutation was not present in 294 control alleles. The waveform of focal macular ERGs recorded from the patient with OMD had a depolarizing pattern, simulating the ERG waveforms observed after the hyperpolarizing bipolar cell activity is blocked.

Conclusions: We have demonstrated in a Japanese patient the possibility that sporadic OMD may also be caused by an RP1L1 mutation. The waveform of focal macular ERGs elicited from the OMD patient with the RP1L1 mutation showed a depolarizing pattern. This characteristic is the same as reported for the focal macular ERGs of OMD.

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DNA analysis for c.3596C>G mutation and deduced amino acids of length polymorphism region of the RP1-like protein 1 (RP1L1) gene and the pedigree of the family with RP1L1 gene mutation. A: Sequence chromatograms for this case (top) and the normal control (bottom) are shown. This case had a c.3596 C>G mutation in exon 4. B: Alignment of S1199 in the RP1L1 family proteins. Amino acid-sequence alignments of RP1L1 from 10 species reported in the NCBI database are shown. Amino acid residues of S1199 in humans and conserved residues from other species are boxed. The asterisks indicate completely conserved residues. S1199 is well conserved in all species reported. C: We confirmed that the mutation in Case 1 was segregated with the disease in one affected member and one unaffected member of the family. D: Deduced amino acids (AA) of repeated regions of the RP1L1 length polymorphism. In this case, one allele contains a 16 AA, and the other allele contains three 16 AA repeats. Variations of amino acids from reference sequence of RP1L1 are shown in red. Those variations are within normal limits.
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f6: DNA analysis for c.3596C>G mutation and deduced amino acids of length polymorphism region of the RP1-like protein 1 (RP1L1) gene and the pedigree of the family with RP1L1 gene mutation. A: Sequence chromatograms for this case (top) and the normal control (bottom) are shown. This case had a c.3596 C>G mutation in exon 4. B: Alignment of S1199 in the RP1L1 family proteins. Amino acid-sequence alignments of RP1L1 from 10 species reported in the NCBI database are shown. Amino acid residues of S1199 in humans and conserved residues from other species are boxed. The asterisks indicate completely conserved residues. S1199 is well conserved in all species reported. C: We confirmed that the mutation in Case 1 was segregated with the disease in one affected member and one unaffected member of the family. D: Deduced amino acids (AA) of repeated regions of the RP1L1 length polymorphism. In this case, one allele contains a 16 AA, and the other allele contains three 16 AA repeats. Variations of amino acids from reference sequence of RP1L1 are shown in red. Those variations are within normal limits.

Mentions: Mutation analysis of the RP1L1 gene in this case showed three missense mutations. There was a c.2578 C>T in exon 4 with a substitution of tryptophan (TGG) for arginine (CGG) at amino acid position 860, a c.3596 C>G in exon 4 with a substitution of cysteine (TGT) for serine (TCT) at amino acid position 1199, and a c. 4484 C>G in exon 4 with a substitution of arginine (CGC) for proline (CCC) at amino acid position 1495. The amino acid substitution at position 860 and 1495 has already been reported in the SNP database and is found in a high percentage of the normal population. A mutation at amino acid position 1199 has not been reported in the SNP database or in earlier reports (Figure 6A). The serine at position 1199 is well conserved among the RP1L1 family in other species (Figure 6B). This mutation was predicted to be probably damaging with a score of 0.999 by PolyPhen-2. The SIFT tool analysis revealed a score of 0 and predicted that the replaced amino acid is potentially damaging and would not be tolerated. PMut predicted that this mutation is pathological. Align GVGD predicted this mutation as class C65, which means it most likely interferes with the protein function. Out of five computational assessments, only MutationTaster predicted this mutation as a polymorphism. We confirmed that the mutation in this case was segregated with the disease in one affected member and one unaffected member of the family (Figure 6C). The unaffected member of the family in Case 1 underwent clinical examination, including BCVAs, slit-lamp biomicroscopy, fundus ophthalmoscopy, OCT, and focal ERGs. All examination findings were normal. This mutation was not present in 300 control alleles. This mutation p.S1199C has been registered in GenBank with accession number AB684329.


A new mutation in the RP1L1 gene in a patient with occult macular dystrophy associated with a depolarizing pattern of focal macular electroretinograms.

Kabuto T, Takahashi H, Goto-Fukuura Y, Igarashi T, Akahori M, Kameya S, Iwata T, Mizota A, Yamaki K, Miyake Y, Takahashi H - Mol. Vis. (2012)

DNA analysis for c.3596C>G mutation and deduced amino acids of length polymorphism region of the RP1-like protein 1 (RP1L1) gene and the pedigree of the family with RP1L1 gene mutation. A: Sequence chromatograms for this case (top) and the normal control (bottom) are shown. This case had a c.3596 C>G mutation in exon 4. B: Alignment of S1199 in the RP1L1 family proteins. Amino acid-sequence alignments of RP1L1 from 10 species reported in the NCBI database are shown. Amino acid residues of S1199 in humans and conserved residues from other species are boxed. The asterisks indicate completely conserved residues. S1199 is well conserved in all species reported. C: We confirmed that the mutation in Case 1 was segregated with the disease in one affected member and one unaffected member of the family. D: Deduced amino acids (AA) of repeated regions of the RP1L1 length polymorphism. In this case, one allele contains a 16 AA, and the other allele contains three 16 AA repeats. Variations of amino acids from reference sequence of RP1L1 are shown in red. Those variations are within normal limits.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3351429&req=5

f6: DNA analysis for c.3596C>G mutation and deduced amino acids of length polymorphism region of the RP1-like protein 1 (RP1L1) gene and the pedigree of the family with RP1L1 gene mutation. A: Sequence chromatograms for this case (top) and the normal control (bottom) are shown. This case had a c.3596 C>G mutation in exon 4. B: Alignment of S1199 in the RP1L1 family proteins. Amino acid-sequence alignments of RP1L1 from 10 species reported in the NCBI database are shown. Amino acid residues of S1199 in humans and conserved residues from other species are boxed. The asterisks indicate completely conserved residues. S1199 is well conserved in all species reported. C: We confirmed that the mutation in Case 1 was segregated with the disease in one affected member and one unaffected member of the family. D: Deduced amino acids (AA) of repeated regions of the RP1L1 length polymorphism. In this case, one allele contains a 16 AA, and the other allele contains three 16 AA repeats. Variations of amino acids from reference sequence of RP1L1 are shown in red. Those variations are within normal limits.
Mentions: Mutation analysis of the RP1L1 gene in this case showed three missense mutations. There was a c.2578 C>T in exon 4 with a substitution of tryptophan (TGG) for arginine (CGG) at amino acid position 860, a c.3596 C>G in exon 4 with a substitution of cysteine (TGT) for serine (TCT) at amino acid position 1199, and a c. 4484 C>G in exon 4 with a substitution of arginine (CGC) for proline (CCC) at amino acid position 1495. The amino acid substitution at position 860 and 1495 has already been reported in the SNP database and is found in a high percentage of the normal population. A mutation at amino acid position 1199 has not been reported in the SNP database or in earlier reports (Figure 6A). The serine at position 1199 is well conserved among the RP1L1 family in other species (Figure 6B). This mutation was predicted to be probably damaging with a score of 0.999 by PolyPhen-2. The SIFT tool analysis revealed a score of 0 and predicted that the replaced amino acid is potentially damaging and would not be tolerated. PMut predicted that this mutation is pathological. Align GVGD predicted this mutation as class C65, which means it most likely interferes with the protein function. Out of five computational assessments, only MutationTaster predicted this mutation as a polymorphism. We confirmed that the mutation in this case was segregated with the disease in one affected member and one unaffected member of the family (Figure 6C). The unaffected member of the family in Case 1 underwent clinical examination, including BCVAs, slit-lamp biomicroscopy, fundus ophthalmoscopy, OCT, and focal ERGs. All examination findings were normal. This mutation was not present in 300 control alleles. This mutation p.S1199C has been registered in GenBank with accession number AB684329.

Bottom Line: The variant c.3596 C>G in exon 4 resulted in the substitution of cysteine for serine at amino acid position 1199.The serine at position 1199 is well conserved among the RP1L1 family in other species.We have demonstrated in a Japanese patient the possibility that sporadic OMD may also be caused by an RP1L1 mutation.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan.

ABSTRACT

Purpose: To determine whether a mutation in the RP1-like protein 1 (RP1L1) gene is present in a Japanese patient with sporadic occult macular dystrophy (OMD) and to examine the characteristics of focal macular electroretinograms (ERGs) of the patient with genetically identified OMD.

Methods: An individual with OMD underwent detailed ophthalmic clinical evaluations including focal macular ERGs. Mutation screening of all coding regions and flanking intron sequences of the RP1L1 gene were performed with DNA sequencing analysis in this case with OMD.

Results: A new RP1L1 mutation (c.3596 C>G in exon 4) was identified. The variant c.3596 C>G in exon 4 resulted in the substitution of cysteine for serine at amino acid position 1199. The serine at position 1199 is well conserved among the RP1L1 family in other species. Four out of five computational assessment tools predicted that this mutation is damaging to the protein function. This mutation was not present in 294 control alleles. The waveform of focal macular ERGs recorded from the patient with OMD had a depolarizing pattern, simulating the ERG waveforms observed after the hyperpolarizing bipolar cell activity is blocked.

Conclusions: We have demonstrated in a Japanese patient the possibility that sporadic OMD may also be caused by an RP1L1 mutation. The waveform of focal macular ERGs elicited from the OMD patient with the RP1L1 mutation showed a depolarizing pattern. This characteristic is the same as reported for the focal macular ERGs of OMD.

Show MeSH
Related in: MedlinePlus