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


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 severity1. 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) gene4,5,6,7. Some correlation has been established between SMN protein levels and disease course8,9,10; 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.

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We thank all the patients and families who have contributed to this study, as well as all clinicians who provided clinical information and samples. We thank A. Burghes and J. McPherson for providing sequences of PAC DJ215P15 and P1 3996, and A. Burghes for cosmid 108H11 and YACs from the SMA region. We are grateful to the members of the International SMA Consortium for stimulating discussions and to the MDA and Families of SMA for fostering collaborations. We would like to recognize D. Bennett, I. Guerrero and J. Scarfo for expert assistance with sequencing and the HHMI biopolymer facility for oligonucleotide synthesis. We are grateful to R. Wirth for programming the SMA patient database and for general computer assistance. Many thanks to E. Gussoni for help with FISH analysis, to J. Haslett for assistance with 4F5rel sequencing and to members of the Kunkel and Engle labs for critical review of this manuscript. Support for the sequencing of mouse BAC 149m19 was kindly provided to W.F.D. by a grant from the Muscular Dystrophy Association. J.M.S. is a Howard Hughes Medical Institute Predoctoral Fellow. B.W. and K.Z. are supported by the Deutsche Forschungsgemeinschaft. L.M.K. is supported by NINDS grant number NS 23740. L.M.K. and W.F.D. are Investigators of the Howard Hughes Medical Institute.

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Correspondence to Louis M. Kunkel.

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Figure 1: H4F5 and M4f5 amino acid sequence, mRNA tissue distribution and alignments to homologous proteins.
Figure 2: Genomic organization of H4F5 relative to existing genes in the SMA critical region.