title: Identification of a Gypsy SHOX mutation (p.A170P) in Léri-Weill dyschondrosteosis and Langer mesomelic dysplasia.
abstract: We report the clinical and molecular characteristics of 12 Spanish families with multiple members affected with Léri-Weill dyschondrosteosis (LWD) or Langer mesomelic dysplasia (LMD), who present the SHOX (short stature homeobox gene) mutation p.A170P (c.508G>C) in heterozygosity or homozygosity, respectively. In all studied families, the A170P mutation co-segregated with the fully penetrant phenotype of mesomelic limb shortening and Madelung deformity. A shared haplotype around SHOX was observed by microsatellite analysis, confirming the presence of a common ancestor, probably of Gypsy origin, as 11 of the families were of this ethnic group. Mutation screening in 359 Eastern-European Gypsies failed to identify any carriers. For the first time, we have shown SHOX expression in the human growth plate of a 22-week LMD fetus, homozygous for the A170P mutation. Although the mutant SHOX protein was expressed in all zones of the growth plate, the chondrocyte columns in the proliferative zone were disorganized with the chondrocytes occurring in smaller columnal clusters. We have also identified a novel mutation at the same residue, c. 509C>A (p.A170D), in two unrelated Spanish LWD families, which similar to A170P mutation impedes nuclear localization of SHOX. In conclusion, we have identified A170P as the first frequent SHOX mutation in Gypsy LWD and LMD individuals.
authors.affiliation: Instituto de Genética Médica y Molecular, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Barca-Tierno
authors.forename: Miriam
authors.initials: M
authors.lastname: Aza-Carmona
authors.forename: Eva
authors.initials: E
authors.lastname: Barroso
authors.forename: Damia
authors.initials: D
authors.lastname: Heine-Suner
authors.forename: Dimitar
authors.initials: D
authors.lastname: Azmanov
authors.forename: Jordi
authors.initials: J
authors.lastname: Rosell
authors.forename: Begoña
authors.initials: B
authors.lastname: Ezquieta
authors.forename: Lucia Sentchordi
authors.initials: LS
authors.lastname: Montané
authors.forename: Teresa
authors.initials: T
authors.lastname: Vendrell
authors.forename: Jaime
authors.initials: J
authors.lastname: Cruz
authors.forename: Fernando
authors.initials: F
authors.lastname: Santos
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Rodríguez
authors.forename: Jesús
authors.initials: J
authors.lastname: Pozo
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gracía
authors.forename: Angel
authors.initials: A
authors.lastname: Campos-Barros
authors.forename: Sara
authors.initials: S
authors.lastname: Benito-Sanz
authors.forename: Karen E
authors.initials: KE
authors.lastname: Heath
mesh_terms: D003241:Consanguinity; D005260:Female; D005333:Fetus / Q000378:metabolism; D018703:Founder Effect; D006130:Growth Disorders / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D006132:Growth Plate / Q000378:metabolism; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation; D010009:Osteochondrodysplasias / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D021381:Protein Transport; D006178:Romani People / Q000235:genetics*; D000074122:Short Stature Homeobox Protein
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein