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Genetics of pain: studies of migraine and pain insensitivity
Umeå University, Faculty of Medicine, Medical Biosciences.
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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1021
Keyword [en]
Migraine, pain insensitivity, susceptibility genes, genome-wide scan, linkage, polymorphism, association, HSAN V, nerve growth factor, neurite outgrowth
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:umu:diva-776ISBN: 91-7264-062-6 (print)OAI: oai:DiVA.org:umu-776DiVA: diva2:144487
Public defence
2006-05-19, Major Groove, 6L, Umeå universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2006-04-27 Created: 2006-04-27 Last updated: 2009-10-26Bibliographically approved
List of papers
1. Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1.
Open this publication in new window or tab >>Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1.
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2002 (English)In: Neurology, ISSN 0028-3878, Vol. 59, no 11, 1804-1807 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-5099 (URN)12473779 (PubMedID)
Available from: 2006-04-27 Created: 2006-04-27 Last updated: 2015-11-02Bibliographically approved
2. 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.
Open this publication in new window or tab >>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.
2006 (English)In: Neuroscience Letters, ISSN 0304-3940, Vol. 396, no 2, 137-142 p.Article in journal (Refereed) Published
Keyword
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
Identifiers
urn:nbn:se:umu:diva-15297 (URN)10.1016/j.neulet.2005.11.039 (DOI)16378686 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2009-10-26Bibliographically approved
3. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.
Open this publication in new window or tab >>A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.
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2004 (English)In: Human Molecular Genetics, ISSN 0964-6906, Vol. 13, no 8, 799-805 p.Article in journal (Refereed) Published
Abstract [en]

Identification of genes associated with pain insensitivity syndromes can increase the understanding of the pathways involved in pain and contribute to the understanding of how sensory pathways relate to other neurological functions. In this report we describe the mapping and identification of the gene responsible for loss of deep pain perception in a large family from northern Sweden. The loss of pain perception in this family is characterized by impairment in the sensing of deep pain and temperature but with normal mental abilities and with most other neurological responses intact. A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients. Thus the cases in this study fall into the class of patients with loss of pain perception with underlying peripheral neuropathy. Clinically they best fit into HSAN V. Using a model of recessive inheritance we identified an 8.3 Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of functional candidate genes in the disease critical region revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype. This NGF mutation seems to separate the effects of NGF involved in development of central nervous system functions such as mental abilities, from those involved in peripheral pain pathways. This mutation could therefore potentially provide an important tool to study different roles of NGF, and of pain control.

Keyword
Adolescent, Adult, Animals, Cattle, Child, Child; Preschool, DNA Mutational Analysis, Female, Guinea Pigs, Humans, Male, Mice, Nerve Growth Factor/*genetics, Pain/*genetics, Pain Insensitivity; Congenital/*genetics, Pedigree, Protein Structure; Secondary, Rats
Identifiers
urn:nbn:se:umu:diva-14121 (URN)10.1093/hmg/ddh096 (DOI)14976160 (PubMedID)
Available from: 2007-09-13 Created: 2007-09-13 Last updated: 2009-11-11Bibliographically approved
4. Mutant Nerve Growth Factor (NGF) – responsible for Hereditary and Sensory Autonomic Neuropathy type V – is defectively secreted and accumulates as proNGF.
Open this publication in new window or tab >>Mutant Nerve Growth Factor (NGF) – responsible for Hereditary and Sensory Autonomic Neuropathy type V – is defectively secreted and accumulates as proNGF.
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-5102 (URN)
Available from: 2006-04-27 Created: 2006-04-27 Last updated: 2010-01-13Bibliographically approved

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