Molecular analysis of cluster headache.
OBJECTIVE
Cluster headache (CH) is characterized by severe, recurrent, unilateral attacks of extreme intensity and brief duration. Variants in a myriad of genes were studied in sporadic CH patients, often with conflicting results.


METHODS
We studied gene mutations in some candidate genes, hypocretin receptor 2, Clock, and alcohol dehydrogenase 4 (ADH4), in 54 unrelated sporadic CH patients and in 200 controls in 8 kindreds/families that included more affected and nonaffected cases. Furthermore, we performed the whole-genome scanning by comparative genomic hybridization, searching for rearrangements associated with DNA gain or loss in a subset of sporadic and familial CH and control participants.


RESULTS
The analysis of candidate genes revealed that only allele and genotype frequency of the 2 ADH4 mutations resulted significantly between sporadic CH and controls; the same mutations were homozygous in CH patients from 2 families. The comparative genomic hybridization analysis revealed 2 novel rearrangements that involved the intron regions of thyrotropin-releasing hormone-degrading enzyme and neurexin 3 (NRXN3) genes, respectively. The first arrangement was present either in CH or in controls, whereas the second one was specifically found in some sporadic and familial CH cases.


CONCLUSIONS
Our data (although obtained on a small number of cases) confirm the genetic heterogeneity of CH, suggesting that mutations in the ADH4 gene and a novel rearrangement involving NRXN3 gene might be related to CH in a subset of cases.
*Dipartimento di Bioscienze e Territorio, Università del Molise, Isernia, Italy †Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy §Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli Federico II, Naples, Italy ∥Dipartimento di Neuroscienze e Scienze Riproduttive e Odontostomatologiche, Università di Napoli Federico II, Naples, Italy ‡CEINGE-Biotecnologie Avanzate, Naples, Italy.
Federica
F
Zarrilli
Rossella
R
Tomaiuolo
Carlo
C
Ceglia
Barbara
B
Lombardo
Barbara
B
Izzo
Giuseppe
G
Castaldo
Lucio
L
Pastore
Roberto
R
De Simone
D000293:Adolescent; D000328:Adult; D000426:Alcohol Dehydrogenase / Q000235:genetics*; D003027:Cluster Headache / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D064446:Orexin Receptors / Q000235:genetics; D055815:Young Adult
D009419:Nerve Tissue Proteins; D064446:Orexin Receptors; C082354:neurexin IIIalpha; D000426:Alcohol Dehydrogenase; C105552:alcohol dehydrogenase IV