title: Maternal uniparental heterodisomy with partial isodisomy of a chromosome 2 carrying a splice acceptor site mutation (IVS9-2A>T) in ALS2 causes infantile-onset ascending spastic paralysis (IAHSP).
abstract: Infantile-onset ascending spastic paralysis (OMIM #607225) is a rare autosomal recessive early onset motor neuron disease caused by mutations in the gene ALS2. We report on a splice acceptor site mutation in intron 9 of ALS2 (IVS9-2A>T) in a German patient from nonconsanguineous parents. The mutation results in skipping of exon 10. This causes a frame-shift in exon 11 and a premature stop codon. Analysis of the parental ALS2 gene revealed heterozygosity for the mutation in the mother but not in the father. Therefore, we studied polymorphic markers scattered along chromosome 2 in both parents and the patient and found maternal uniparental disomy in the patient. While homozygosity was observed at several loci of chromosome 2 including ALS2, other loci were heterozygous, i.e., both maternal alleles were present. The findings can be explained by at least four recombination events during maternal meiosis followed by a meiosis I error and postzygotic trisomy rescue or gamete complementation.
authors.affiliation: Institut für Humangenetik, Justus-Liebig-Universität, Giessen, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Herzfeld
authors.forename: Nicole
authors.initials: N
authors.lastname: Wolf
authors.forename: Pia
authors.initials: P
authors.lastname: Winter
authors.forename: Holger
authors.initials: H
authors.lastname: Hackstein
authors.forename: Daniel
authors.initials: D
authors.lastname: Vater
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000503:physiopathology; D001483:Base Sequence; D002675:Child, Preschool; D002889:Chromosomes, Human, Pair 2; D004252:DNA Mutational Analysis; D005260:Female; D005819:Genetic Markers; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011247:Pregnancy; D022821:RNA Splice Sites; D024182:Uniparental Disomy
chemical_list: C438187:ALS2 protein, human; D005819:Genetic Markers; D020662:Guanine Nucleotide Exchange Factors; D022821:RNA Splice Sites