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Exclusion of the juvenile myoclonic epilepsy gene EFHC1 as the cause of migraine on chromosome 6, but association to two rare polymorphisms in MEP1A and RHAG.
Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
2006 (English)In: Neuroscience Letters, ISSN 0304-3940, Vol. 396, no 2, 137-142 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2006. Vol. 396, no 2, 137-142 p.
Keyword [en]
Blood Proteins/*genetics, Calcium-Binding Proteins/*genetics, Chromosome Aberrations, Chromosomes; Human; Pair 6/*genetics, DNA Mutational Analysis, Female, Gene Deletion, Genetic Predisposition to Disease/epidemiology/*genetics, Heterozygote, Humans, Incidence, Male, Membrane Glycoproteins/*genetics, Metalloendopeptidases/*genetics, Migraine Disorders/epidemiology/*genetics, Multigene Family/genetics, Pedigree, Polymorphism; Single Nucleotide/genetics, Sweden/epidemiology
URN: urn:nbn:se:umu:diva-15297DOI: 10.1016/j.neulet.2005.11.039PubMedID: 16378686OAI: diva2:154969
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2009-10-26Bibliographically approved
In thesis
1. Genetics of pain: studies of migraine and pain insensitivity
Open this publication in new window or tab >>Genetics of pain: studies of migraine and pain insensitivity
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pain is a major public health issue throughout the world. Increased understanding of the different forms of pain and identification of susceptibility genes could contribute to improved treatments. The main aims of this thesis were to identify the underlying genetic causes of pain by studying two large families affected with migraine and pain insensitivity, respectively.

Migraine is one of the most common neurovascular disorders, affecting over 12% of the western population. The genetic contribution to migraine is about 50% according to family and twin studies. To identify novel susceptibility loci for migraine, we performed a genome-wide screen in a large family with migraine from northern Sweden. Linkage analysis revealed significant evidence of linkage (LOD=5.41) on chromosome 6p12.2-p21.1. A predisposing haplotype spanning 10 Mb was inherited with migraine in all affected members of the pedigree. Further fine-mapping of multiple SNP markers restricted the disease critical region to 8.5 Mb. Nine candidate genes were sequenced, revealing no disease-associated polymorphisms in SLC29A1, CLIC5, PLA2G7, IL17, SLC25A27 and TNFRSF21, but rare novel polymorphisms segregating with the disease haplotype in EFHC1, RHAG and MEP1A. EFHC1 has recently been shown to be involved in epilepsy, which is interesting considering the link between migraine and epilepsy. However, association analysis of EFHC1 revealed no difference between patients and controls, suggesting that this gene is not a risk factor for migraine. The combination of the two polymorphisms in RHAG and MEP1A could, however, not be found in any control individuals, indicating that they might be involved in genetic predisposition to migraine in this family.

Disorders with reduced pain sensitivity are very rare, since pain perception is essential for survival. A number of disorders have still been identified with pain insensitivity and peripheral nerve degeneration as major clinical signs, including the hereditary sensory and autonomic neuropathies (HSAN). In order to identify novel susceptibility genes for HSAN V, we performed a genome-wide screen in a large consanguineous pedigree from a small village in northern Sweden. A homozygous region identical-by-descent was identified on chromosome 1p11.2-p13.2 in the three most severely affected patients. Subsequent analysis of candidate genes revealed a missense mutation in a conserved region of the nerve growth factor beta (NGFB) gene, causing a drastic amino acid change (R211W) in the NGF protein. NGF is important for the development and maintenance of the sympathetic and sensory nervous system and is therefore likely to be involved in disease. Functional analysis revealed that mutant NGF failed to induce neurite outgrowth and cell differentiation in PC12 cells. Furthermore, almost no mutant NGF was secreted by COS-7 cells, indicating that the processing and/or secretion of the protein might be disrupted.

In conclusion, these findings present a novel migraine locus on chromosome 6 and identification of two rare polymorphisms that might be risk factors for migraine. Furthermore, a mutation in NGFB was found to cause complete loss of deep pain perception, which represents a very interesting model system to study pain mechanisms.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2006. 70 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1021
Migraine, pain insensitivity, susceptibility genes, genome-wide scan, linkage, polymorphism, association, HSAN V, nerve growth factor, neurite outgrowth
National Category
Medical Genetics
urn:nbn:se:umu:diva-776 (URN)91-7264-062-6 (ISBN)
Public defence
2006-05-19, Major Groove, 6L, Umeå universitet, Umeå, 13:00 (English)
Available from: 2006-04-27 Created: 2006-04-27 Last updated: 2009-10-26Bibliographically approved

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