Identification of a Gypsy SHOX mutation (p.A170P) in Léri-Weill dyschondrosteosis and Langer mesomelic dysplasia

Verónica Barca-Tierno, Miriam Aza-Carmona, Eva Barroso, Damia Heine-Suner, Dimitar Azmanov, Jordi Rosell, Begõa Ezquieta, Lucia Sentchordi Montané, Teresa Vendrell, Jaime Cruz, Fernando Santos, José Ignacio Rodríguez, Jess Pozo, Jess Argente, Luba Kalaydjieva, Ricardo Gracía, Ngel Campos-Barros, Sara Benito-Sanz, Karen E. Heath

    Research output: Contribution to journalArticleResearchpeer-review

    8 Citations (Scopus)

    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.508GC) 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. 509CA (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. © 2011 Macmillan Publishers Limited All rights reserved.
    Original languageEnglish
    Pages (from-to)1218-1225
    JournalEuropean Journal of Human Genetics
    Volume19
    Issue number12
    DOIs
    Publication statusPublished - 1 Dec 2011

    Keywords

    • !SHOX; A170P; A170D; Léri-Weill dyschondrosteosis; Langer mesomelic dysplasia; founder

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