Loss-of-Function Mutations in Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome
Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a “second hit,” that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.
Vyšlo v časopise:
Loss-of-Function Mutations in Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome. PLoS Genet 7(4): e32767. doi:10.1371/journal.pgen.1002050
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002050
Souhrn
Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a “second hit,” that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.
Zdroje
1. BovéeJVMG 2008 Multiple osteochondromas. Orphanet journal of rare diseases 3 3
2. CouvineauAWoutersVBertrandGRouyerCGérardB 2008 PTHR1 mutations associated with Ollier disease result in receptor loss of function. Hum Mol Genet 17 2766 2775
3. PansuriyaTCKroonHMBovéeJVMG 2010 Enchondromatosis: insights on the different subtypes. Int J Clin Exp Pathol 3 557 569
4. SilveCJüppnerH 2006 Ollier disease. Orphanet journal of rare diseases 1 37
5. MaroteauxP 1971 [Metachondromatosis]. Z Kinderheilkd 109 246 261
6. KennedyLA 1983 Metachondromatosis. Radiology 148 117 118
7. BassettGSCowellHR 1985 Metachondromatosis. Report of four cases. The Journal of bone and joint surgery American volume 67 811 814
8. IkegawaSNaganoAMatsushitaTNakamuraK 1992 Metachondromatosis: a report of two cases in a family. Nippon Seikeigeka Gakkai Zasshi 66 460 466
9. HermanTEChinesAMcAlisterWHGottesmanGSEddyMC 1997 Metachondromatosis: report of a family with facial features mildly resembling trichorhinophalangeal syndromePediatr Radiol 1997 Nov;27(11):864. Pediatric radiology 27 436 441
10. BovéeJVMGHameetmanLKroonHMAignerTHogendoornPCW 2006 EXT-related pathways are not involved in the pathogenesis of dysplasia epiphysealis hemimelica and metachondromatosis. J Pathol 209 411 419
11. SobreiraNLMCirulliETAvramopoulosDWohlerEOswaldGL 2010 Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS Genet 6 e1000991 doi:10.1371/journal.pgen.1000991
12. ShawBA 1996 Resolving neonatal osteochondroma: a case report and literature review. Am J Orthop 25 226 228
13. KeretDBassettGS 1990 Avascular necrosis of the capital femoral epiphysis in metachondromatosis. Journal of pediatric orthopedics 10 658 661
14. WengerDRBirchJRathjenKTobinRBillmanG 1991 Metachondromatosis and avascular necrosis of the femoral head: a radiographic and histologic correlation. Journal of pediatric orthopedics 11 294 300
15. HunterAGKozlowskiKHochbergerO 1995 Metachondromatosis. Can Assoc Radiol J 46 202 208
16. MavrogenisAFSkarpidiEPapakonstantinouOPapagelopoulosPJ 2010 Chondrosarcoma in metachondromatosis: a case report. The Journal of bone and joint surgery American volume 92 1507 1513
17. AbecasisGRChernySSCooksonWOCardonLR 2002 Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30 97 101
18. BovéeJVCleton-JansenAMWuytsWCaethovenGTaminiauAH 1999 EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet 65 689 698
19. LupskiJRReidJGGonzaga-JaureguiCRio DeirosDChenDCY 2010 Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med 362 1181 1191
20. RoachJCGlusmanGSmitAFAHuffCDHubleyR 2010 Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328 636 639
21. JorgeAALMalaquiasACArnholdIJPMendoncaBB 2009 Noonan syndrome and related disorders: a review of clinical features and mutations in genes of the RAS/MAPK pathway. Horm Res 71 185 193
22. KontaridisMISwansonKDDavidFSBarfordDNeelBG 2006 PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem 281 6785 6792
23. TartagliaMZampinoGGelbBD 2010 Noonan syndrome: clinical aspects and molecular pathogenesis. Mol Syndromol 1 2 26
24. GrossmannKSRosárioMBirchmeierCBirchmeierW 2010 The tyrosine phosphatase Shp2 in development and cancer. Adv Cancer Res 106 53 89
25. JonesKBPiomboVSearbyCKurrigerGYangB 2010 A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes. Proc Natl Acad Sci USA
26. BaulerTJKamiyaNLapinskiPELangewischEMishinaY 2010 Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations. Dis Model Mech
27. SaxtonTMHenkemeyerMGascaSShenRRossiDJ 1997 Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. EMBO J 16 2352 2364
28. DenayerEDevriendtKde RavelTVan BuggenhoutGSmeetsE 2010 Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations. Genes Chromosomes Cancer 49 242 252
29. GrossmannKSWendeHPaulFECheretCGarrattAN 2009 The tyrosine phosphatase Shp2 (PTPN11) directs Neuregulin-1/ErbB signaling throughout Schwann cell development. Proc Natl Acad Sci USA 106 16704 16709
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 4
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