Letter | Published:

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

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. 1

    Munsat, T.L. & Davies, K.E. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromusc. Disord. 2, 423–428 (1992).

  2. 2

    Brzustowicz, L.M. et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature 344, 540–541 (1990).

  3. 3

    Melki, J. et al. Mapping of acute (type I) spinal muscular atrophy to chromosome 5q12-q14. Lancet 336, 271–273 (1990).

  4. 4

    Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155–165 (1995).

  5. 5

    Rodrigues, N.R. et al. Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy. Hum. Mol. Genet. 4, 631–634 (1995).

  6. 6

    Hahnen, E., Schonling, J., Rudnik-Schoneborn, S., Zerres, K. & Wirth, B. Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease. Am. J. Hum. Genet. 59, 1057–1065 (1996).

  7. 7

    van der Steege, G. et al. Apparent gene conversions involving the SMN gene in the region of the spinal muscular atrophy locus on chromosome 5. Am. J. Hum. Genet. 59, 834–838 (1996).

  8. 8

    Lefebvre, S. et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nature Genet. 16, 265–269 (1997).

  9. 9

    Coovert, D.D. et al. The survival motor neuron protein in spinal muscular atrophy. Hum. Mol. Genet. 6, 1205–1214 (1997).

  10. 10

    Lorson, C.L. et al. SMN oligomerization defect correlates with spinal muscular atrophy severity. Nature Genet. 19, 63–66 (1998).

  11. 11

    Scharf, J.M. et al. The mouse region syntenic for human spinal muscular atrophy lies within the Lgn1 critical interval and contains multiple copies of Naip exon 5. Genomics 38, 405–417 (1996).

  12. 12

    Thompson, T.G. Physical and transcriptional mapping of human chromosome 5q12-q13, the region containing the gene for spinal muscular atrophy. Thesis, Univ. California, Irvine (1996).

  13. 13

    Mortillaro, M.J. & Berezney, R. Matrin CYP, an SR-rich cyclophilin that associates with the nuclear matrix and splicing factors. J. Biol. Chem. 273, 8183–8192 (1998).

  14. 14

    Liu, Q., Fischer, U., Wang, F. & Dreyfuss, G. The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell 90, 1013–1021 (1997).

  15. 15

    Fischer, U., Liu, Q. & Dreyfuss, G. The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis. Cell 90, 1023–1029 (1997).

  16. 16

    DiDonato, C.J. et al. Association between Ag1-CA alleles and severity of autosomal recessive proximal spinal muscular atrophy. Am. J. Hum. Genet. 55, 1218–1229 (1994).

  17. 17

    Wirth, B. et al. Allelic association and deletions in autosomal recessive spinal muscular atrophy: association of marker genotype with disease severity and candidate cDNAs. Hum. Mol. Genet. 4, 1273–1284 (1995).

  18. 18

    Burlet, P. et al. Large scale deletions of the 5q13 region are specific to Werdnig-Hoffmann disease. J. Med. Genet. 33, 281–283 (1996).

  19. 19

    Velasco, E., Valero, C., Valero, A., Moreno, F. & Hernandez-Chico, C. Molecular analysis of the SMN and NAIP genes in Spanish spinal muscular atrophy (SMA) families and correlation between number of copies of (C)BCD541 and SMA phenotype. Hum. Mol. Genet. 5, 257–263 (1996).

  20. 20

    McAndrew, P.E. et al. Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. Am. J. Hum. Genet. 60, 1411–1422 (1997).

  21. 21

    Nishio, H. et al. Decreased expression of full-length mRNA for cBCD41 does not correlate with spinal muscular atrophy phenotype severity. Neurology 48, 1266–1270 (1997).

  22. 22

    Schwartz, M. et al. Quantification, by solid-phase minisequencing, of the telomeric and centromeric copies of the survival motor neuron gene in families with spinal muscular atrophy. Hum. Mol. Genet. 6, 99–104 (1997).

  23. 23

    Roy, N. et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80, 167–178 (1995).

  24. 24

    Burglen, L. et al. The gene encoding p44, a subunit of the transcription factor TFIIH, is involved in large-scale deletions associated with Werdnig-Hoffmann disease. Am. J. Hum. Genet. 60, 72–79 (1997).

  25. 25

    Carter, T.A. et al. A multicopy transcription-repair gene, BTF2p44, maps to the SMA region and demonstrates SMA associated deletions. Hum. Mol. Genet. 6, 229–236 (1997).

  26. 26

    Chen, Q. et al. Sequence of a 131-kb region of 5q13.1 containing the spinal muscular atrophy candidate genes SMN and NAIP. Genomics 48, 121–127 (1998).

  27. 27

    Melki, J. et al. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science 264, 1474–1477 (1994).

  28. 28

    Harris, N.L. Genotator: a workbench for sequence annotation. Genome Res. 7, 754–762 (1997).

  29. 29

    Selig, S. et al. Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene. Proc. Natl Acad. Sci. USA 92, 3702–3706 (1995).

  30. 30

    Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

Download references

Acknowledgements

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.

Author information

Correspondence to Louis M. Kunkel.

Rights and permissions

Reprints and Permissions

About this article

Further reading

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.