title: 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.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Camacho-Vanegas
authors.forename: Sandra Catalina
authors.initials: SC
authors.lastname: Camacho
authors.forename: Jacob
authors.initials: J
authors.lastname: Till
authors.forename: Irene
authors.initials: I
authors.lastname: Miranda-Lorenzo
authors.forename: Esteban
authors.initials: E
authors.lastname: Terzo
authors.forename: Maria Celeste
authors.initials: MC
authors.lastname: Ramirez
authors.forename: Vern
authors.initials: V
authors.lastname: Schramm
authors.forename: Grace
authors.initials: G
authors.lastname: Cordovano
authors.forename: Giles
authors.initials: G
authors.lastname: Watts
authors.forename: Sarju
authors.initials: S
authors.lastname: Mehta
authors.forename: Virginia
authors.initials: V
authors.lastname: Kimonis
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hoch
authors.forename: Keith D
authors.initials: KD
authors.lastname: Philibert
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Raabe
authors.forename: David F
authors.initials: DF
authors.lastname: Bishop
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Glucksman
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D001848:Bone Diseases, Developmental / Q000235:genetics*; D001859:Bone Neoplasms / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D005091:Exons; D016678:Genome; D018219:Histiocytoma, Benign Fibrous / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000235:genetics; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D011323:Primates / Q000235:genetics; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics*; D012509:Sarcoma / Q000235:genetics
chemical_list: D007527:Isoenzymes; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase