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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

Funduscopic appearance of patients with Wolfram syndrome. Shown are fundus photographs from (A) 19-year-old case 1 (OD) and from (B) 14-year-old case 3 (OS). Both photographs reveal severe waxy pallor of the optic disc.
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f1: Funduscopic appearance of patients with Wolfram syndrome. Shown are fundus photographs from (A) 19-year-old case 1 (OD) and from (B) 14-year-old case 3 (OS). Both photographs reveal severe waxy pallor of the optic disc.

Mentions: This was a 19-year-old male, the oldest of the four brothers, who was given a diagnosis of diabetes mellitus type 1 when he was 10 years old. He came to our hospital complaining of decreased vision. At examination, his visual acuity was 20/400 that improved after refraction to 20/300 in the right eye, and 3/200 that improved to 20/400 in the left eye. The pupils were mydriatic with decreased light reflex. Right optic nerve head showed a cup to disc ratio of 0.45 and severe pallor (Figure 1A). Microhemorrhages in the macular area were also evident; left optic nerve head had a cup to disc ratio of 0.25 and severe pallor. Goldmann Kinetic Perimetry (GKP) showed concentric reduction of 20 to 30 degrees mainly at the nasal sector of the visual field as well as an enlarged blind spot. Retinal fluorangiography (FAG) was normal in both eyes. Audiometric studies showed low-frequency hearing loss. Dental examination showed enamel hypoplasia and abnormal teeth color.


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

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

Funduscopic appearance of patients with Wolfram syndrome. Shown are fundus photographs from (A) 19-year-old case 1 (OD) and from (B) 14-year-old case 3 (OS). Both photographs reveal severe waxy pallor of the optic disc.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Funduscopic appearance of patients with Wolfram syndrome. Shown are fundus photographs from (A) 19-year-old case 1 (OD) and from (B) 14-year-old case 3 (OS). Both photographs reveal severe waxy pallor of the optic disc.
Mentions: This was a 19-year-old male, the oldest of the four brothers, who was given a diagnosis of diabetes mellitus type 1 when he was 10 years old. He came to our hospital complaining of decreased vision. At examination, his visual acuity was 20/400 that improved after refraction to 20/300 in the right eye, and 3/200 that improved to 20/400 in the left eye. The pupils were mydriatic with decreased light reflex. Right optic nerve head showed a cup to disc ratio of 0.45 and severe pallor (Figure 1A). Microhemorrhages in the macular area were also evident; left optic nerve head had a cup to disc ratio of 0.25 and severe pallor. Goldmann Kinetic Perimetry (GKP) showed concentric reduction of 20 to 30 degrees mainly at the nasal sector of the visual field as well as an enlarged blind spot. Retinal fluorangiography (FAG) was normal in both eyes. Audiometric studies showed low-frequency hearing loss. Dental examination showed enamel hypoplasia and abnormal teeth color.

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