Molecular characteristics

Molecular Characteristics

The ASPH gene is located at 8q12.1 and encodes three proteins, junctin, junctate, and ASPH. ASPH (aspartyl/asparaginyl β-hydroxylase) has been found to hydroxylate aspartate and asparagine residues on epidermal growth factor (EGF)-domain-containing proteins. ASPH is highly expressed in the snout, limbs, and eye of mouse embryos.

Mutations and pathophysiology

Patel et al. (2014) identified two different mutations affecting three individuals from three unrelated families with facial dysmorphism, lens dislocation, anterior segment abnormalities, and spontaneous filtering blebs.

One individual was affected by a homozygous 5bp indel (c.1852_1856delinsGGG [RefSeq NM_004318.3]), predicted to cause a frameshift with premature truncation (p.Asn618Glyfs*20). However, PT-PCR revealed that this indel results in the complete skipping of exon 22 (r.1765_1900del), causing a frameshift (p.Ser589Glufs*18), most likely because it removes an exon splicing element.

The other two individuals were affected by a homozygous missense variant (c.2203C>T [RefSeq NM_004318.3]) causing p.Arg735Trp. Arg735 was found to be a critical residue in the formation of a pair of salt-bridge interactions with the 2-oxoglutarate cofactor, which enables substrate recruitment to the catalytic site and is essential in the catalytic reaction. p.Arg735Trp would disrupt the cofactor binding as a result of the loss of the critical salt bridges and potential clashes with the hydrophobic side chain of Trp.