Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy

• Published in: Journal of medical genetics Vol. 41; no. 3; pp. 183 - 187
• Main Authors: Garcia, C C, Blair, H J, Seager, M, Coulthard, A, Tennant, S, Buddles, M, Curtis, A, Goodship, J A
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.03.2004; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Adolescent; Adult; Age; Aggressiveness; Base Sequence; Behavior; Biological and medical sciences; Chromosome Mapping; Chromosomes, Human, X - genetics; Convulsions & seizures; Deoxyribonucleic acid; DNA; Epilepsy; Epilepsy - complications; Epilepsy - genetics; Epilepsy - physiopathology; Female; Haplotypes - genetics; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Learning disabilities; Male; Medical sciences; mental handicap; Microsatellite Repeats - genetics; Middle Aged; Molecular Sequence Data; Monoamine Oxidase - genetics; Mutation; Mutation - genetics; Nervous system (semeiology, syndromes); Neurology; NMR; Nuclear magnetic resonance; Pedigree; Phenotype; Polymorphism, Genetic - genetics; Short Report; synapsin I; Synapsins - genetics; Synaptic Vesicles - chemistry; X linkage; Nervous system diseases; Family study; Epilepsy; Central nervous system disease; Identification; Mutation; Protein; Cerebral disorder
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2003.013680

A four generation family is described in which some men of normal intelligence have epilepsy and others have various combinations of epilepsy, learning difficulties, macrocephaly, and aggressive behaviour. As the phenotype in this family is distinct from other X linked recessive disorders linkage studies were carried out. Linkage analysis was done using X chromosome microsatellite polymorphisms to define the interval containing the causative gene. Genes from within the region were considered possible candidates and one of these, SYN1, was screened for mutations by direct DNA sequencing of amplified products. Microsatellite analysis showed that the region between MAOB (Xp11.3) and DXS1275 (Xq12) segregated with the disease. Two point linkage analysis demonstrated linkage with DXS1039, lod score 4·06 at θ = 0, and DXS991, 3·63 at θ = 0. Candidate gene analysis led to identification of a nonsense mutation in the gene encoding synapsin I that was present in all affected family members and female carriers and was not present in 287 control chromosomes. Synapsin I is a synaptic vesicle associated protein involved in the regulation of synaptogenesis and neurotransmitter release. The SYN1 nonsense mutation that was identified is the likely cause of the phenotype in this family.