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 Lé ri-Weill dyschondrosteosis (LWD) or Langer mesomelic dysplasia (LMD), who present the SHOX (short stature homeobox gene) mutation p.A170P (c.508G4C) 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. 509C4A (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.

Radiological signs of Léri-Weill dyschondrosteosis present in the A170P carrier

“…Thus, in my opinion, the conclusions in this paper are misleading since it is stated that the studied patient did not have radiological traits nor bone dysplasia in contrast to all previously reported A170P carriers,3 4 who were reported to have dysplastic features. Furthermore, in the discussion it is suggested that this ‘mutation shows a highly variable penetrance ’ .…”

“…Furthermore, in the discussion it is suggested that this ‘mutation shows a highly variable penetrance ’ . This statement, however, is not sufficiently supported by the data presented and is at odds with our own previous data,3 because as mentioned previously, the patient's x-ray does reveal radiological/dysplastic signs characteristic of LWD, and no anthropometrical examination was undertaken to explore mesomelic shortening and finally, most importantly, clinical and molecular analysis was not undertaken in other family members, which would have been indicated and very useful to properly assess penetrance.…”

A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies

“…The population of European Gypsies is about 10 million; with more than 500,000 individuals in Spain, Slovakia, Hungary, Bulgaria and Romania . Many Mendelian disorders in European Gypsies are caused by private founder mutations and specifically in Spain and Portugal, about a dozen genetic diseases are highly prevalent in this ethnic group . In this study, we detected a new founder mutation in EIF2AK4 [c.3344C>T; (p.P1115L)] (Fig.…”

A170P mutation inSHOXgene in a patient not presenting with Madelung deformity: Figure 1

“…Barca-Tierno et al (2011) have characterised 12 Spanish families affected with LWS or LMD, where 11 of them belong to the gypsy population. The authors state that A170P mutation is fully penetrant because it cosegregates with the phenotype of mesomelic limb shortening and Madelung deformity 8. Sabherwal et al presented a family with 17 members affected with LWD and LMD, all of them carrying the A170P mutation and all but one presenting with the Madelung deformity.…”