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).
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.
Herzfeld
Thilo
T
Institut für Humangenetik, Justus-Liebig-Universität, Giessen, Germany.
Wolf
Nicole
N
Winter
Pia
P
Hackstein
Holger
H
Vater
Daniel
D
Müller
Ulrich
U
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
C438187:ALS2 protein, human; D005819:Genetic Markers; D020662:Guanine Nucleotide Exchange Factors; D022821:RNA Splice Sites