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Familial Wolfram syndrome due to compound heterozygosity for two novel WFS1 mutations.

Zenteno JC, Ruiz G, Pérez-Cano HJ, Camargo M - Mol. Vis. (2008)

Bottom Line: Direct WFS1 analysis disclosed a paternally inherited novel missense R177P mutation whereas allele-specific cloning and sequencing revealed a novel WFS1 16 bp deletion that was inherited from the mother.This is the first documented case of the molecular basis of the disease in a Latin American family.Analysis of more patients from this population will establish if compound heterozygosity is commonly found in affected individuals from this ethnic group.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Conde de Valenciana, Mexico City, Mexico. jczenteno@institutodeoftalmologia.org

ABSTRACT

Purpose: To describe the first instance of genotyping in a Latin American family with Wolfram syndrome (WS).

Methods: Four affected siblings and their healthy parents were studied. Ophthalmologic examination included best corrected visual acuity determination, funduscopy, fluorescein retinal angiography, and Goldmann kinetic perimetry. Molecular methods included linkage analysis using microsatellites markers located on the markers located on the Wofram syndrome 1 (WFS1) region at 4p16.1, PCR amplification and direct nucleotide sequencing analysis of the complete coding region and exon/intron junctions of WFS1. In addition, allele-specific cloning and sequencing techniques were used to characterize a heterozygous frameshift mutation.

Results: The four affected siblings presented with a homogeneous clinical picture characterized by early onset diabetes mellitus, severe optic atrophy, and progressive hearing loss. Linkage analysis indicated that all four sibs were heterozygous for markers linked to the WFS1 region and that each inherited the same allele from the mother and the same from the father, suggesting compound heterozygosity. Direct WFS1 analysis disclosed a paternally inherited novel missense R177P mutation whereas allele-specific cloning and sequencing revealed a novel WFS1 16 bp deletion that was inherited from the mother.

Conclusions: Our report of two novel WFS1 mutations expands the molecular spectrum of Wolfram syndrome. This is the first documented case of the molecular basis of the disease in a Latin American family. Analysis of more patients from this population will establish if compound heterozygosity is commonly found in affected individuals from this ethnic group.

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Related in: MedlinePlus

WFS1 gene novel frameshift mutation in WS. Exon 8 sequence analysis revealed that a normal tract of 16 bp (boxed in A) is heterozygously deleted in DNA from an affected subject (case 1) (B). The deletion predicts the introduction of a premature stop signal 65 codons downstream residue 451 of Wolframin.
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f4: WFS1 gene novel frameshift mutation in WS. Exon 8 sequence analysis revealed that a normal tract of 16 bp (boxed in A) is heterozygously deleted in DNA from an affected subject (case 1) (B). The deletion predicts the introduction of a premature stop signal 65 codons downstream residue 451 of Wolframin.

Mentions: The clinical association of early onset diabetes mellitus and progressive optic atrophy suggested the diagnosis of WS in the four affected siblings from this family. As a first screening analysis, we performed linkage analysis to the WFS1 locus at 4p16.1 by means of genotyping of markers D4S432, D4S3023, DS2366, and D4S2639. Visual inspection of the haplotypes revealed that all four affected siblings were heterozygous for the four markers as each parent consistently transmitted to their progeny the same WFS1-linked haplotype (Figure 2). These results strongly suggested WFS1 compound heterozygosity as the source of the disease. Nucleotide sequencing of the entire WFS1 coding region confirmed the presence of two different mutations in the four affected patients: one allele carried a novel R177P missense mutation resulting from a G>C transversion at nucleotide position 530 in exon 5 (Figure 3). This missense mutation was present heterozygously also in DNA from the father. Exon 8 DNA from the four affected siblings exhibited an overlapping pattern on automated DNA sequencing indicating the presence of a frameshift mutation. Allele-specific sequencing of a fragment of exon 8 allowed the identification of a novel 16 bp deletion, 1355–1370delAGC CCT ACA CGC GCA G (c.1354del16), that predicts the introduction of a premature stop signal 65 codons downstream, P451fsX515 (Figure 4). Maternal DNA analysis demonstrated that the mother carried this 16 bp deletion in a heterozygous state.


Familial Wolfram syndrome due to compound heterozygosity for two novel WFS1 mutations.

Zenteno JC, Ruiz G, Pérez-Cano HJ, Camargo M - Mol. Vis. (2008)

WFS1 gene novel frameshift mutation in WS. Exon 8 sequence analysis revealed that a normal tract of 16 bp (boxed in A) is heterozygously deleted in DNA from an affected subject (case 1) (B). The deletion predicts the introduction of a premature stop signal 65 codons downstream residue 451 of Wolframin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483297&req=5

f4: WFS1 gene novel frameshift mutation in WS. Exon 8 sequence analysis revealed that a normal tract of 16 bp (boxed in A) is heterozygously deleted in DNA from an affected subject (case 1) (B). The deletion predicts the introduction of a premature stop signal 65 codons downstream residue 451 of Wolframin.
Mentions: The clinical association of early onset diabetes mellitus and progressive optic atrophy suggested the diagnosis of WS in the four affected siblings from this family. As a first screening analysis, we performed linkage analysis to the WFS1 locus at 4p16.1 by means of genotyping of markers D4S432, D4S3023, DS2366, and D4S2639. Visual inspection of the haplotypes revealed that all four affected siblings were heterozygous for the four markers as each parent consistently transmitted to their progeny the same WFS1-linked haplotype (Figure 2). These results strongly suggested WFS1 compound heterozygosity as the source of the disease. Nucleotide sequencing of the entire WFS1 coding region confirmed the presence of two different mutations in the four affected patients: one allele carried a novel R177P missense mutation resulting from a G>C transversion at nucleotide position 530 in exon 5 (Figure 3). This missense mutation was present heterozygously also in DNA from the father. Exon 8 DNA from the four affected siblings exhibited an overlapping pattern on automated DNA sequencing indicating the presence of a frameshift mutation. Allele-specific sequencing of a fragment of exon 8 allowed the identification of a novel 16 bp deletion, 1355–1370delAGC CCT ACA CGC GCA G (c.1354del16), that predicts the introduction of a premature stop signal 65 codons downstream, P451fsX515 (Figure 4). Maternal DNA analysis demonstrated that the mother carried this 16 bp deletion in a heterozygous state.

Bottom Line: Direct WFS1 analysis disclosed a paternally inherited novel missense R177P mutation whereas allele-specific cloning and sequencing revealed a novel WFS1 16 bp deletion that was inherited from the mother.This is the first documented case of the molecular basis of the disease in a Latin American family.Analysis of more patients from this population will establish if compound heterozygosity is commonly found in affected individuals from this ethnic group.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Conde de Valenciana, Mexico City, Mexico. jczenteno@institutodeoftalmologia.org

ABSTRACT

Purpose: To describe the first instance of genotyping in a Latin American family with Wolfram syndrome (WS).

Methods: Four affected siblings and their healthy parents were studied. Ophthalmologic examination included best corrected visual acuity determination, funduscopy, fluorescein retinal angiography, and Goldmann kinetic perimetry. Molecular methods included linkage analysis using microsatellites markers located on the markers located on the Wofram syndrome 1 (WFS1) region at 4p16.1, PCR amplification and direct nucleotide sequencing analysis of the complete coding region and exon/intron junctions of WFS1. In addition, allele-specific cloning and sequencing techniques were used to characterize a heterozygous frameshift mutation.

Results: The four affected siblings presented with a homogeneous clinical picture characterized by early onset diabetes mellitus, severe optic atrophy, and progressive hearing loss. Linkage analysis indicated that all four sibs were heterozygous for markers linked to the WFS1 region and that each inherited the same allele from the mother and the same from the father, suggesting compound heterozygosity. Direct WFS1 analysis disclosed a paternally inherited novel missense R177P mutation whereas allele-specific cloning and sequencing revealed a novel WFS1 16 bp deletion that was inherited from the mother.

Conclusions: Our report of two novel WFS1 mutations expands the molecular spectrum of Wolfram syndrome. This is the first documented case of the molecular basis of the disease in a Latin American family. Analysis of more patients from this population will establish if compound heterozygosity is commonly found in affected individuals from this ethnic group.

Show MeSH
Related in: MedlinePlus