Identification of a candidate modifying gene for spinal muscular atrophy by comparative genomics

• Published in: Nature genetics Vol. 20; no. 1; pp. 83 - 86
• Main Authors: Kunkel, Louis M, Scharf, Jeremiah M, Endrizzi, Matthew G, Wetter, Axel, Huang, Sidong, Thompson, Terri G, Zerres, Klaus, Dietrich, William F, Wirth, Brunhilde
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.1998; Nature Publishing Group
• Subjects: Agriculture; Amino Acid Sequence; Animal Genetics and Genomics; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chromosome Mapping; Chromosomes, Human, Pair 5; Cloning, Molecular; Cyclic AMP Response Element-Binding Protein; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Gene Deletion; Gene Function; Genetic Markers; Homozygote; Human Genetics; Humans; letter; Medical sciences; Mice; Molecular Sequence Data; Muscular Atrophy, Spinal - genetics; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; RNA-Binding Proteins; Sequence Homology, Amino Acid; SMN Complex Proteins; Survival of Motor Neuron 1 Protein; Human; Neuromuscular diseases; Nervous system diseases; Nucleotide sequence; Spinal amyotrophy; Homology; Modifier gene; Gene expression; Genetic disease; Central nervous system disease; Phenotype variation; Degenerative disease; Differential expression; Spinal cord disease
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/1753

Spinal muscular atrophy (SMA) is a common recessive disorder characterized by the loss of lower motor neurons in the spinal cord. The disease has been classified into three types based on age of onset and severity 1 . SMA I-III all map to chromosome 5q13 (Refs 2 , 3 ), and nearly all patients display deletions or gene conversions of the survival motor neuron ( SMN1 ) gene 4 , 5 , 6 , 7 . Some correlation has been established between SMN protein levels and disease course 8 , 9 , 10 ; nevertheless, the genetic basis for SMA phenotypic variability remains unclear, and it has been postulated that the loss of an additional modifying factor contributes to the severity of type I SMA. Using comparative genomics to screen for such a factor among evolutionarily conserved sequences between mouse and human, we have identified a novel transcript, H4F5 , which lies closer to SMN1 than any previously identified gene in the region. A multi-copy microsatellite marker that is deleted in more than 90% of type I SMA chromosomes is embedded in an intron of this gene, indicating that H4F5 is also highly deleted in type I SMA chromosomes, and thus is a candidate phenotypic modifier for SMA.