Enhancer elements upstream of the SHOX gene are active in the developing limb

Area of Science:

• Genetics
• Developmental Biology
• Skeletal Disorders

Background:

• Léri-Weill Dyschondrosteosis (LWD) is a dominant skeletal disorder.
• SHOX gene mutations and downstream regulatory element deletions cause LWD via haploinsufficiency.
• SHOX is a homeodomain transcription factor crucial for limb development.

Purpose of the Study:

• To analyze the regulatory significance of the genomic region upstream of the SHOX gene.
• To identify potential regulatory elements controlling SHOX expression in limb development.
• To investigate the role of upstream SHOX deletions in LWD pathogenesis.

Main Methods:

• Comparative genomic analysis to identify conserved non-coding elements upstream of SHOX.
• In ovo enhancer assays in chicken limb bud and cornea to test enhancer activity.
• Screening of LWD patients for deletions in the SHOX upstream region.

Main Results:

• Three conserved non-coding elements exhibited enhancer activity specifically in the developing chicken limb.
• No enhancer activity was detected in the developing chicken cornea.
• No deletions in the identified upstream enhancer region were found in 60 LWD patients with intact SHOX coding and downstream regions.

Conclusions:

• The region upstream of SHOX contains limb-specific enhancers potentially regulating SHOX expression.
• SHOX upstream deletions appear to be infrequent in LWD patients, suggesting they are not a common cause.
• The lower frequency of upstream deletions may be due to genomic structure or result in distinct phenotypes.