Allelic background of LEPRE1 mutations that cause recessive forms of osteogenesis imperfecta in different populations

Area of Science:

• Genetics
• Molecular Biology
• Human Population Studies

Background:

• Biallelic mutations in the LEPRE1 gene cause recessively inherited osteogenesis imperfecta (OI), frequently leading to perinatal lethality.
• A specific LEPRE1 mutation (c.1080+1G>T) is prevalent in African Americans, with origins traced to West African populations in Ghana and Nigeria.

Purpose of the Study:

• To investigate the carrier frequency of the c.1080+1G>T LEPRE1 mutation in an African-derived population in Tobago.
• To explore LEPRE1 allelic diversity within this population and its potential contribution to OI.
• To correlate identified LEPRE1 mutations with clinical outcomes in individuals with OI.

Main Methods:

• Population-based carrier frequency analysis of the c.1080+1G>T LEPRE1 mutation in 200 Tobago samples.
• Review of neonatal death records in Trinidad over a 3-year period.
• Sequence analysis to identify LEPRE1 allelic variants and mutations in individuals with OI.

Main Results:

• The carrier frequency of c.1080+1G>T in Tobago was approximately 1/200 and did not correlate with recorded neonatal deaths.
• High LEPRE1 allelic diversity (11 variants) was observed in Tobago, reflecting ancestral origins.
• Identified mutations in 44 OI patients occurred on seven of these 11 variant alleles, often causing mRNA or protein instability.

Conclusions:

• The c.1080+1G>T LEPRE1 mutation does not appear to significantly impact neonatal mortality in Tobago.
• High LEPRE1 allelic diversity in Tobago suggests complex population genetics and potential founder effects.
• Unidentified missense mutations in LEPRE1 may contribute to milder forms of osteogenesis imperfecta.