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

Olga Camacho-Vanegas, Sandra Catalina Camacho, Jacob Till, Irene Miranda-Lorenzo, Esteban Terzo, Maria Celeste Ramirez, Vern L. 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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)614-627
Number of pages14
JournalAmerican Journal of Human Genetics
Volume90
Issue number4
DOIs
StatePublished - Apr 6 2012

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Developmental Bone Disease
Bone Neoplasms
Muscular Dystrophies
Primates
Exons
Genome
Mutation
Genes
Protein Isoforms
Bone Development
Alternative Splicing
Polyamines
Muscular Diseases
Adenine
Tumor Suppressor Genes
Sarcoma
Methionine
Bone and Bones
Enzymes
Diaphyseal medullary stenosis with malignant fibrous histiocytoma

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Primate genome gain and loss : A bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts. / Camacho-Vanegas, Olga; Camacho, Sandra Catalina; Till, Jacob; Miranda-Lorenzo, Irene; Terzo, Esteban; Ramirez, Maria Celeste; Schramm, Vern L.; Cordovano, Grace; Watts, Giles; Mehta, Sarju; Kimonis, Virginia; Hoch, Benjamin; Philibert, Keith D.; Raabe, Carsten A.; Bishop, David F.; Glucksman, Marc J.; Martignetti, John A.

In: American Journal of Human Genetics, Vol. 90, No. 4, 06.04.2012, p. 614-627.

Research output: Contribution to journalArticle

Camacho-Vanegas, O, Camacho, SC, Till, J, Miranda-Lorenzo, I, Terzo, E, Ramirez, MC, Schramm, VL, Cordovano, G, Watts, G, Mehta, S, Kimonis, V, Hoch, B, Philibert, KD, Raabe, CA, Bishop, DF, Glucksman, MJ & Martignetti, JA 2012, 'Primate genome gain and loss: A bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts', American Journal of Human Genetics, vol. 90, no. 4, pp. 614-627. https://doi.org/10.1016/j.ajhg.2012.02.024
Camacho-Vanegas, Olga ; Camacho, Sandra Catalina ; Till, Jacob ; Miranda-Lorenzo, Irene ; Terzo, Esteban ; Ramirez, Maria Celeste ; Schramm, Vern L. ; Cordovano, Grace ; Watts, Giles ; Mehta, Sarju ; Kimonis, Virginia ; Hoch, Benjamin ; Philibert, Keith D. ; Raabe, Carsten A. ; Bishop, David F. ; Glucksman, Marc J. ; Martignetti, John A. / Primate genome gain and loss : A bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 4. pp. 614-627.
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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.",
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AU - Miranda-Lorenzo, Irene

AU - Terzo, Esteban

AU - Ramirez, Maria Celeste

AU - Schramm, Vern L.

AU - Cordovano, Grace

AU - Watts, Giles

AU - Mehta, Sarju

AU - Kimonis, Virginia

AU - Hoch, Benjamin

AU - Philibert, Keith D.

AU - Raabe, Carsten A.

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