title: Genetic studies of Polish migraine patients: screening for causative mutations in four migraine-associated genes.
abstract: OBJECTIVE
  Migraine is the most common neurological disorder, affecting approximately 12 % of the adult population worldwide, caused by both environmental and genetic factors. Three causative genes have been identified in familial hemiplegic migraine (FHM) families: CACNA1A, ATP1A2, and SCNA1A. Recently, several mutations in KCNK18 have also been found as causative factors in migraine development. The aim of our study was to identify the genetic background of migraine in the Polish population.
  
  
  METHODS
  Sixty patients with migraine without aura (MO) or with different types of migraine with aura (MA), including sporadic hemiplegic, familial hemiplegic, and probable familial hemiplegic, were screened for mutations in the four genes previously linked with different types of migraine (ATP1A2, CACNA1A, SCN1A, and KCNK18).
  
  
  RESULTS
  Two missense mutations were found. One novel mutation in SCN1A, encoding α subunit of sodium channel, causing amino acid change M1500V localized to a region encoding inactivation loop between transmembrane domains III and IV of the channel, was detected in a female FHM patient. The M1500V mutation was absent in a group of 62 controls, as well as in the ExAC database. The second, already known missense mutation S231P in KCNK18 was found in a female MA patient. Additionally, a novel intronic polymorphism possibly affecting alternative splicing of SCN1A, at chr2:16685249, g.77659T>C, and c.4581+32A>G, located between exons 24 and 25, in a region encoding the inactivation loop of the sodium channel was found in a female MO patient. No mutations in ATP1A2 or CACNA1A were found in the study group.
  
  
  CONCLUSIONS
  The presence of SCN1A mutations and absence of mutations in ATP1A2 or CACNA1A suggest that the Polish patients represent FHM type 3. On the other hand, the presence of KCNK18 mutation indicated another FHM subtype. It could be speculated that contrary to other European populations, the genetic basis of migraine in the Polish population involves mutations in genes not included in the study. Next-generation sequencing methods should be implemented to identify other migraine-associated variants.
authors.affiliation: Department of Neurology, Warsaw Medical University, 61 Żwirki i Wigury Street, 02-091, Warsaw, Poland. idomitrz@wum.edu.pl.
authors.forename: Izabela
authors.initials: I
authors.lastname: Domitrz
authors.affiliation: Department of Neurology, Warsaw Medical University, 61 Żwirki i Wigury Street, 02-091, Warsaw, Poland. mkosiorek@imdik.pan.pl.|Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre PAS, 5 Pawinskiego Street, 02-106, Warsaw, Poland. mkosiorek@imdik.pan.pl.
authors.forename: Michalina
authors.initials: M
authors.lastname: Kosiorek
authors.affiliation: Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre PAS, 5 Pawinskiego Street, 02-106, Warsaw, Poland. c.zekanowski@imdik.pan.pl.
authors.forename: Cezary
authors.initials: C
authors.lastname: Żekanowski
authors.affiliation: Department of Neurology, Warsaw Medical University, 61 Żwirki i Wigury Street, 02-091, Warsaw, Poland. amkaminska@wum.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Kamińska
mesh_terms: D000328:Adult; D015220:Calcium Channels / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000235:genetics*; D020325:Migraine with Aura / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; D009363:Neoplasm Proteins; D015221:Potassium Channels; D012097:Repressor Proteins; D000254:Sodium-Potassium-Exchanging ATPase; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C476574:KCNK18 protein, human; C516477:NACC1 protein, human; C498531:ATP1A2 protein, human