An ~140-kb deletion associated with feline spinal muscular atrophy implies an essential LIX1 function for motor neuron survival (original) (raw)

  1. John C. Fyfe1,7,8,
  2. Marilyn Menotti-Raymond2,7,
  3. Victor A. David2,
  4. Lars Brichta3,
  5. Alejandro A. Schäffer4,
  6. Richa Agarwala4,
  7. William J. Murphy5,
  8. William J. Wedemeyer6,
  9. Brittany L. Gregory1,
  10. Bethany G. Buzzell2,
  11. Meghan C. Drummond1,
  12. Brunhilde Wirth3, and
  13. Stephen J. O'Brien2
  14. 1Laboratory of Comparative Medical Genetics, Department of Microbiology & Molecular Genetics, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824, USA;
  15. 2Laboratory of Genomic Diversity, National Cancer Institute–Frederick, Frederick, Maryland 21702, USA;
  16. 3Institute of Human Genetics, Institute of Genetics, and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany;
  17. 4National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20894, USA;
  18. 5Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas 77843, USA;
  19. 6Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA
  20. ↵7 These two authors contributed equally to this work.

Abstract

The leading genetic cause of infant mortality is spinal muscular atrophy (SMA), a clinically and genetically heterogeneous group of disorders. Previously we described a domestic cat model of autosomal recessive, juvenile-onset SMA similar to human SMA type III. Here we report results of a whole-genome scan for linkage in the feline SMA pedigree using recently developed species-specific and comparative mapping resources. We identified a novel SMA gene candidate, LIX1, in an ~140-kb deletion on feline chromosome A1q in a region of conserved synteny to human chromosome 5q15. Though LIX1 function is unknown, the predicted secondary structure is compatible with a role in RNA metabolism. LIX1 expression is largely restricted to the central nervous system, primarily in spinal motor neurons, thus offering explanation of the tissue restriction of pathology in feline SMA. An exon sequence screen of 25 human SMA cases, not otherwise explicable by mutations at the SMN1 locus, failed to identify comparable LIX1 mutations. Nonetheless, a _LIX1_-associated etiology in feline SMA implicates a previously undetected mechanism of motor neuron maintenance and mandates consideration of LIX1 as a candidate gene in human SMA when SMN1 mutations are not found.

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