TY - JOUR
T1 - Primate genome gain and loss
T2 - A bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts
AU - Camacho-Vanegas, Olga
AU - Camacho, Sandra Catalina
AU - Till, Jacob
AU - Miranda-Lorenzo, Irene
AU - Terzo, Esteban
AU - Ramirez, Maria Celeste
AU - Schramm, Vern
AU - Cordovano, Grace
AU - Watts, Giles
AU - Mehta, Sarju
AU - Kimonis, Virginia
AU - Hoch, Benjamin
AU - Philibert, Keith D.
AU - Raabe, Carsten A.
AU - Bishop, David F.
AU - Glucksman, Marc J.
AU - Martignetti, John A.
PY - 2012/4/6
Y1 - 2012/4/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84859517357&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2012.02.024
DO - 10.1016/j.ajhg.2012.02.024
M3 - Article
C2 - 22464254
AN - SCOPUS:84859517357
SN - 0002-9297
VL - 90
SP - 614
EP - 627
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -