Identifying the Locus for the Wolfram (WFS2) Gene

 

Patrick Koske-McBride

 

BBSI

Virginia Commonwealth University

Richmond, Virginia

Introduction:

            Wolfram Syndrome is an autosomal recessive neurodegenerative disorder, sometimes called “DIDMOAD” (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness).  In addition to these symptoms, individuals with Wolfram’s often suffer cognitive disorders such as paranoid delusions, hallucinations, severe depression and increased levels of psychiatric hospitalization.  Wolfram Syndrome is extremely rare.(1)

            The gene responsible for Wolfram’s (WFS1) has already been identified.(2)  However, a recent study revealed that there is a second gene responsible for Wolfram’s on chromosome 4q22-24, but the exact gene is still unknown.  The goal of this project is to identify the second Wolfram’s gene (WFS2).(3)  To do this, we will be searching from marker D4S1591 to marker D4S3240.  This area is comprised of 200,956 base pairs (4) and 53 candidate genes.  Nineteen genes in this area have already been characterized and eliminated as the potential WFS2 gene.  The genes that will be sequenced range from those responsible for cellular pH maintenance to genes that maintain lipid production.  20 of the genes in this segment have not been characterized.  Some of the genes show high degrees of expression in the brain, some in cancer, most genes in this segment are not highly expressed at all.

Methods:

            We will use the Polymerase Chain Reaction (PCR) to clone the coding segments of the remaining candidate genes from the DNA of a known affected individual and a known unaffected individual.  After cloning the segments, we will run single stranded conformational polymorphism (SSCP) analysis on both samples.  The SSCP analysis, while being similar to a standard electrophoresis analysis, is capable of detecting a single base change, making it an effective method for detecting unknown mutations.(5)

            Any regions that show differences compared to each other will be sequenced to determine the specific nucleotide sequence.

Possible Results and Implications:

As technology advances, knowledge of the genetic causes of Wolfram’s may allow us to develop gene therapy for the syndrome.  In addition, genetic screening will be possible.

However, due to the rarity of Wolfram’s, these are not the primary benefits of the study.  Studying Wolfram’s Syndrome may give us insight into linkage and expression of its symptoms: diabetes, deafness and the related neural and psychiatric abnormalities.  A greater understanding of these diseases will lead to a better understanding of these complex common disorders.

Sources:

1. Minton et al.  “Wolfram Syndrome.”  Reviews in Endocrine and Metabolic Disorders.  4 (2003): 53-59.

2. Strom et al.  “Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutation in a novel gene (wolframin) coding a predicted transmembane protein.”  Human Molecular Genetics. 7 (1998): 2021-2028.

3. El-Shanti, et al.: “Homozygosity Mapping Identifies an Additional Locus for Wolfram Syndrome on Chromosome 4q.”  American Journal of Human Genetics.  66:1229-1236

4.  “Human chr4:110,051,831-110,252786 – UCSC Genome Browser v109.” [Online] Available http://genome.ucsc.edu/cgi-bin/hgTracks June 22, 2005.

5. Orita et al. “Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms.”  Proceedings of the National Academy of Sciences of the United States of America.  86 (April 1989): 2766-2770.