title: Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.
abstract: 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.
authors.affiliation: Department of Orthopaedic Surgery, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Margot E
authors.initials: ME
authors.lastname: Bowen
authors.forename: Eric D
authors.initials: ED
authors.lastname: Boyden
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Holm
authors.forename: Belinda
authors.initials: B
authors.lastname: Campos-Xavier
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Judith V
authors.initials: JV
authors.lastname: Bovée
authors.forename: Twinkal C
authors.initials: TC
authors.lastname: Pansuriya
authors.forename: Sérgio B
authors.initials: SB
authors.lastname: de Sousa
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
authors.forename: Elena
authors.initials: E
authors.lastname: Andreucci
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
authors.forename: Livia
authors.initials: L
authors.lastname: Garavelli
authors.forename: Caroline
authors.initials: C
authors.lastname: Pottinger
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ogino
authors.forename: Akinori
authors.initials: A
authors.lastname: Sakai
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Regazzoni
authors.forename: Wim
authors.initials: W
authors.lastname: Wuyts
authors.forename: Luca
authors.initials: L
authors.lastname: Sangiorgi
authors.forename: Elena
authors.initials: E
authors.lastname: Pedrini
authors.forename: Mei
authors.initials: M
authors.lastname: Zhu
authors.forename: Harry P
authors.initials: HP
authors.lastname: Kozakewich
authors.forename: James R
authors.initials: JR
authors.lastname: Kasser
authors.forename: Jon G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Kurek
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Warman
mesh_terms: D002877:Chromosomes, Human / Q000235:genetics; D056915:DNA Copy Number Variations; D004687:Enchondromatosis / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005097:Exostoses, Multiple Hereditary / Q000235:genetics*; D017353:Gene Deletion; D008040:Genetic Linkage; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11