Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts.

Abstract

Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is an autosomal-dominant syndrome characterized by bone dysplasia, myopathy, and bone cancer. We previously mapped the DMS-MFH tumor-suppressing-gene locus to chromosomal region 9p21-22 but failed to identify mutations in known genes in this region. We now demonstrate that DMS-MFH results from mutations in the most proximal of three previously uncharacterized terminal exons of the gene encoding methylthioadenosine phosphorylase, MTAP. Intriguingly, two of these MTAP exons arose from early and independent retroviral-integration events in primate genomes at least 40 million years ago, and since then, their genomic integration has gained a functional role. MTAP is a ubiquitously expressed homotrimeric-subunit enzyme critical to polyamine metabolism and adenine and methionine salvage pathways and was believed to be encoded as a single transcript from the eight previously described exons. Six distinct retroviral-sequence-containing MTAP isoforms, each of which can physically interact with archetype MTAP, have been identified. The disease-causing mutations occur within one of these retroviral-derived exons and result in exon skipping and dysregulated alternative splicing of all MTAP isoforms. Our results identify a gene involved in the development of bone sarcoma, provide evidence of the primate-specific evolution of certain parts of an existing gene, and demonstrate that mutations in parts of this gene can result in human disease despite its relatively recent origin.

• Authors: Olga Camacho-Vanegas, Sandra Catalina Camacho, Jacob Till, Irene Miranda-Lorenzo, Esteban Terzo, Maria Celeste Ramirez, Vern Schramm, Grace Cordovano, Giles Watts, Sarju Mehta, Virginia Kimonis, Benjamin Hoch, Keith D Philibert, Carsten A Raabe, David F Bishop, Marc J Glucksman, John A Martignetti
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 90 Issue 4 Pg. 614-27 (Apr 06 2012) ISSN: 1537-6605 [Electronic] United States
• PMID: 22464254 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Isoenzymes
• Purine-Nucleoside Phosphorylase
• 5'-methylthioadenosine phosphorylase

Topics

• Alternative Splicing (genetics)
• Animals
• Base Sequence
• Biological Evolution
• Bone Diseases, Developmental (genetics)
• Bone Neoplasms (genetics)
• Chromosomes, Human, Pair 9 (genetics)
• Exons
• Genome
• Histiocytoma, Benign Fibrous (genetics)
• Humans
• Isoenzymes (genetics)
• Molecular Sequence Data
• Muscular Dystrophies (genetics)
• Mutation
• Neoplastic Syndromes, Hereditary (genetics)
• Primates (genetics)
• Purine-Nucleoside Phosphorylase (genetics)
• Retroviridae (genetics)
• Sarcoma (genetics)