Familial segregation of a VSX1 mutation adds a new dimension to its role in the causation of keratoconus

PURPOSE To look for segregation of Visual System Homeobox 1 (VSX1) mutations in family members of a patient with keratoconus. METHODS Our initial molecular genetic studies conducted to identify the role of VSX1 in the causation of keratoconus had identified a novel mutation in one patient. He later presented to the clinic affected with vernal kerato conjunctivitis (VKC) accompanied by his brother, also similarly affected. All the family members were called and detailed clinical evaluations were undertaken. DNA from the blood samples of all family members was amplified using primers specific for VSX1 and analyzed by direct sequencing to look for segregation of the mutation in the family members. Protein modeling studies were done to assess the effect of the mutation on protein structure and function. RESULTS Clinical examination of the family revealed bilateral keratoconus and VKC in the proband and his brother. One of his sisters had VKC without keratoconus and his parents and another sister were normal. Molecular analysis identified the VSX1 mutation Q175H in the affected brother and in the mother who had neither VKC nor keratoconus but only the VSX1 Q175H sequence change. CONCLUSIONS The VSX1 Q175H mutation may be a pathogenic variant with incomplete penetrance. Protein modeling studies show that the mutation affects the DNA binding properties of the protein. This VSX1 variant exhibiting low penetrance may require the presence of some modifier genes or environmental factors for disease presentation. VSX1 may have an important role in the pathogenesis of keratoconus which needs further investigation.