Identification of Candidate Genes in Four Human Disorders

The aim of this thesis has been to identify genes and gene regions underlying four different disorders. In papers I-IV, positional cloning methods, such as linkage, association and haplotype analysis have been used for the identification of genomic regions associated with the ichthyosis prematurity syndrome (IPS), adult-onset autosomal dominant leukodystrophy (ADLD) and Kostmann disease.IPS is a rare autosomal recessive skin disorder, which includes a premature birth of the affected child. We mapped the IPS locus to a region on chromosome 9q34, and within this region a haplotype is shared by IPS patients, which suggests a strong founder effect. The haplotype spans 76 kb, which includes four known genes. No sequence or mRNA expression alterations could be detected for the four genes in IPS patients.A candidate region for an adult-onset leukodystrophy (ADLD) on chromosome 5 was investigated in a large Swedish family with ADLD. A significant multipoint LOD score of 9.45 was obtained for markers in the chromosome 5 region and fine-mapping of recombination events restricts a candidate gene region to 1.5 Mb.Kostmann disease is an autosomal recessive form of severe congenital neutropenia. We have identified a 1.2 Mb region on chromosome 1q22 associated with the disease in the original Kostmann family. The region contains 37 genes…


The human genome
Genetic variation
The transcriptome
Inherited diseases
Disease causing mutations
Identifying human disease genes
Genetic linkage
Genetic markers
Linkage analysis
Association study
Haplotype analysis
Expression microarray analysis
Present investigations
Ichthyosis Prematurity Syndrome (IPS)
Adult-onset Autosomal Dominant Leukodystrophy (ADLD)
Kostmann disease
Autistic Disorder (AD)
Ichthyosis Prematurity Syndrome (IPS)
Paper I: Assignment of the locus for ichthyosis prematurity syndrome
to chromosome 9q33.3-34.13
Perspectives on paper I
Paper II: A founder mutation for ichthyosis prematurity syndrome restricted to 76 kb by haplotype association
Perspectives on paper II
Adult-onset autosomal dominant leukodystrophy (ADLD)
Paper III: Adult-onset autosomal dominant leukodystrophy with
autonomic symptoms restricted to 1.5 Mbp on chromosome 5q23
Perspectives on paper III
Kostmann disease
Paper IV: Assignment of the gene locus for severe congenital
neutropenia to chromosome 1q22 in the original Kostmann family
Perspectives on paper IV
Autistic disorder (AD)
Paper V: Constitutional downregulation of SEMA5A expression in autism
Perspectives on paper V
Concluding remarks

Author: Melin, Malin

Source: Uppsala University Library

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