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Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1.
Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.ORCID-id: 0000-0002-3822-0725
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2002 (Engelska)Ingår i: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 59, nr 11, s. 1804-1807Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Migraine is the most common type of chronic episodic headache. To find novel susceptibility genes for familial migraine with and without aura, a genomewide screen was performed in a large family from northern Sweden. Evidence of linkage was obtained on chromosome 6p12.2-p21.1, with a maximum two-point lod score of 5.41 for marker D6S452. The patients with migraine shared a common haplotype of 10 Mb between markers D6S1650 and D6S1960.

Ort, förlag, år, upplaga, sidor
Lippincott Williams & Wilkins, 2002. Vol. 59, nr 11, s. 1804-1807
Nationell ämneskategori
Neurologi
Identifikatorer
URN: urn:nbn:se:umu:diva-5099DOI: 10.1212/01.WNL.0000036617.04943.96ISI: 000179669000031PubMedID: 12473779OAI: oai:DiVA.org:umu-5099DiVA, id: diva2:144483
Tillgänglig från: 2006-04-27 Skapad: 2006-04-27 Senast uppdaterad: 2019-01-23Bibliografiskt granskad
Ingår i avhandling
1. Genetics of pain: studies of migraine and pain insensitivity
Öppna denna publikation i ny flik eller fönster >>Genetics of pain: studies of migraine and pain insensitivity
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Medicinsk biovetenskap, 2006. s. 70
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1021
Nyckelord
Migraine, pain insensitivity, susceptibility genes, genome-wide scan, linkage, polymorphism, association, HSAN V, nerve growth factor, neurite outgrowth
Nationell ämneskategori
Medicinsk genetik
Identifikatorer
urn:nbn:se:umu:diva-776 (URN)91-7264-062-6 (ISBN)
Disputation
2006-05-19, Major Groove, 6L, Umeå universitet, Umeå, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2006-04-27 Skapad: 2006-04-27 Senast uppdaterad: 2018-01-13Bibliografiskt granskad

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Carlsson, AnnaForsgren, LarsHellman, UrbanHolmberg, Dan

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Carlsson, AnnaForsgren, LarsHellman, UrbanHolmberg, Dan
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Umeå centrum för molekylär medicin (UCMM)Klinisk neurovetenskapMedicinsk och klinisk genetikInstitutionen för molekylärbiologi (Medicinska fakulteten)
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