In an Indian family in which 5 of 9 sibs, the offspring of unaffected first-cousin parents, had retinitis pigmentosa (RP4; 613731), Kumaramanickavel et al. (1994) found a G-to-A transition at codon 150 of the RHP gene, predicted to lead to a change from glutamate (GAG) to lysine (AAG) in the gene product. The 4 patients available for study were homozygous for the E150K mutation and 2 of the unaffected 4 sibs were heterozygous. (In the diagram of the pedigree, the order of the sibs was deliberately scrambled to disguise the identity of the heterozygotes.) Glu150 forms part of the second cytoplasmic loop of rhodopsin. Of the more than 60 RP-causing rhodopsin mutations identified, only one, cys140-to-ser, was located in the cytoplasmic loop (Macke et al., 1993).
The E150K mutation in rhodopsin is located in its second cytoplasmic loop and is positioned at the rhodopsin dimer interface. Zhu et al. (2006) showed that neither global protein folding nor G-protein binding and activation by rhodopsin were significantly affected by the E150K mutation. However, E150K rhodopsin was aberrantly glycosylated and was retained in the cis/medial Golgi compartment. E150K rhodopsin did not alter plasma membrane targeting of wildtype rhodopsin in transfected HEK293 cells, and in the presence of excess wildtype rhodopsin, E150K rhodopsin was cotransported with wildtype rhodopsin through the trans-Golgi and delivered to the plasma membrane.
In a Turkish brother and sister with an unusual RP phenotype, Van Schil et al. (2016) identified homozygosity for the E150K mutation in the RHO gene. In addition, the sibs were homozygous for 4 noncoding variants in the SAMD7 gene (620493) that showed reduced activity compared to wildtype SAMD7 in luciferase experiments and electroporation assays in retinal explants. Their unaffected mother and 2 unaffected sisters were heterozygous for the RHO and SAMD7 variants, as was a brother with minor subclinical manifestations. The authors suggested that the unusual nummular intraretinal pigment deposits observed in the affected sibs might be attributed to the SAMD7 variants, and postulated the presence of other modifying factors to account for the heterozygous brother's manifestations.
