Shears, Deborah Jane; (2002) Phenotypic characterisation and molecular genetic analysis of Leri-Weill dyschondrosteosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Leri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterised by disproportionate short stature, with shortening of the middle (mesomelic) segments of the limbs, associated with the Madelung deformity of the wrist. Using a positional candidate approach, LWD, which was previously thought to show autosomal dominant inheritance, has been mapped to the major pseudoautosomal region of the X and Y chromosomes, and shown to be caused by mutation or hemizygous deletion of the short stature homeobox gene SHOX. Most cases of LWD are shown to be due to a microdeletion encompassing SHOX. Five different point mutations in SHOX have been identified. Four of these are nonsense mutations causing premature stop codons resulting in truncation of the protein. One missense mutation has been identified in the homeobox, which may reduce the stability of the interaction between the SHOX homeodomain and its DNA target(s). A more severe mesomelic skeletal dysplasia, Langer mesomelic dysplasia (LMD), was proposed on clinical grounds as the homozygous form of LWD and this has been confirmed by the molecular analysis of three cases of LMD. A clinical study including detailed limb length measurements of individuals affected with LWD from 10 families has demonstrated that there is very variable expression, and that females are significantly more severely affected than males particularly in final adult height and in forearm length. The study has identified that shortening of the upper arm (rhizomelia) is also a feature of LWD. Functional analysis of SHOX has been undertaken using the yeast two-hybrid system to identify potential protein-protein interactions involving SHOX. The recently identified transcription factor Dlxin-1 was identified as a potential SHOX interactor, and evidence from GST affinity capture assays to support this interaction is presented.

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