title: A novel ALS2 splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family.
abstract: BACKGROUND
  Primary lateral sclerosis (PLS) is a rare neurodegenerative disease that affects the upper motor neurons of the CNS. Juvenile-onset PLS (JPLS) is inherited in an autosomal recessive mode and is also found in sporadic cases. A consanguineous Cypriot family with three affected individuals presenting with JPLS was identified and studied.
  
  
  METHODS
  Patients were clinically evaluated and samples were taken from consenting family members. All available family members were genotyped and linkage analysis at marker loci spanning the wider region of the ALS2 gene was performed. Selected exons of the ALS2 gene were sequenced and RNA analysis was performed using available lymphoblastoid cell lines from the proband.
  
  
  RESULTS
  All affected individuals presented in the second year of life with progressive upper motor neuron dysfunction, affecting both bulbar and extremity muscles. Severity was variable, with two of the patients remaining ambulatory in the second and fifth decade of life while the third one was never able to walk. A novel ALS2 homozygous c.2980-2A>G mutation at the splice acceptor site of intron 17 was identified and its effect was confirmed at the RNA level.
  
  
  CONCLUSIONS
  This novel ALS2 splice-site mutation is causing the loss of exon 18 in the transcript which results in a frameshift after exon 17. This frameshift most probably introduces a stop codon seven amino acids further down the new reading frame (p.993fsX7) and is expected to lead to a premature stop in exon 19 thus leading to a truncated protein after translation.
authors.affiliation: The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, Ayios Dhometios, 2370 Nicosia, Cyprus.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Mintchev
authors.forename: Eleni
authors.initials: E
authors.lastname: Zamba-Papanicolaou
authors.forename: Kleopas A
authors.initials: KA
authors.lastname: Kleopa
authors.forename: Kyproula
authors.initials: K
authors.lastname: Christodoulou
mesh_terms: D000293:Adolescent; D000328:Adult; D003535:Cyprus; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*
chemical_list: C438187:ALS2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D022821:RNA Splice Sites