LRPAP1 (Low Density Lipoprotein Receptor-Related Protein-Associated Protein 1) gene is located at 4p16.3 and encodes a chaperone of lipoprotein receptor-associated proteins (LRP1 and LRP2) and inhibit ligand binding to LRP1 and LRP2 and thus inhibits the degradation of these proteins. Knockout mouse models show decreased expression of LRP in the liver and brain, which in turn is association with increased transforming growth factor (TGF)-β levels. Because increased TGF-β can modulate the extracellular matrix of the sclera, this may be a mechanism by which LRPAP1 mutations lead to long axial lengths. Indeed, Aldahmesh et al. (2013) showed that there was more than 2-fold increase in TGF-β levels in cells with LRPAP1 mutations.
Mutations and pathophysiology
Aldahmesh et al. (2013) reported homozygosity for a truncating mutation (c.605delA [p.Asn202Thrfs*8]) in one family and another truncating mutation (c.863_864del [p.Ile288Argfs*118]) in two other families affected by this disorder.
Jiang et al. (2015) reported homozygosity for c.199delC [p.Q67Sfs*8] in a Chinese 5-year old boy.
Khan et al. (2016) reported six families, which harbored the mutation c.863_864del [p.Ile288Argfs*118] and one family that harbored the mutation c.605del [p.Asn202Thrfs*8]. Mutation results for 3 of these families were previously reported.
In a large cohort of 187 high myopia patients, Feng et al. (2017) reported homozygosity for LRPAP1 mutations, c.605delA [p.Asn202Thrfs*8] and c.863_864del [p.Ile288Argfs*118].
As mentioned above, LRPAP1 mutations are associated with an increase in TGF-β levels, which can modulate the extracellular matrix of the sclera and cause increased axial length, possibly explaining the associated LRPAP1 pathology.