Molecular characteristics
The MPDZ (Multiple PDZ Domain Protein) gene is located at 9p23 and encodes a tight junction protein that interacts with the C-terminal sequences of specific ion channel subunits and G protein-coupled receptors. It has been found to localize to tight junctions where it is hypothesized to scaffold and attract other proteins for proper tight junction formation.
Mutations and pathophysiology
Mutations in MPDZ alter proper tight junction formation. Abnormal cell-cell adhesion seems to be the likely pathological mechanism behind HYC2.
Al-Dosari et al. (2013) reported a homozygous c.628C>T mutation in MPDZ resulting in premature truncation of the protein p.(Gln210*). The affected patients came from a consanguineous Saudi family and displayed the phenotypical features of HYC2. The same founder mutation was also identified in a stillborn with HYC2 from another family.
Shaheen et al. (2017) reported the same p.(Gln210*) mutation in the affected members of 3 consanguineous Saudi families. Three other new mutations in MPDZ were also identified:
- A homozygous c.4469delA mutation causing frameshift and premature termination, p. (Gln1490Argfs*19). The affected patient was born of consanguineous Palestinian parents with HYC2.
- A compound heterozygous nonsense mutation (c.2230C>T, p. (Arg744*) and c.3211C>T, p. (Arg1071*)) was identified in an 9-year-old boy of European descent affected with HYC2.
- A homozygous c.5278 G>A, p. (Ala1760Thr) mutation was reported in an affected 15-month-old male from Kuwait.