LCA is a major concern among different types of inherited retinal blindness due to its devastating severity (1). Although genetic consulting for consanguine parents is highly recommended, we are still witnessing the birth of babies with congenital disorders (1, 3, 12). So far, studies on genetic defects of LCA indicated that about 70% of patients suffered from a molecular disease-causing event. As the recent efforts focused on the new therapeutic strategies such as gene replacement therapy, finding the underlying genetic problem in affected patients is a very important issue (1).
Hence, in this study, we investigated for the disease-causing mutation in a 1-year-old affected girl, who was referred to medical genetics for no light perception (NLP) blindness. The patient was belonging to consanguineous healthy parents with no history of inherited disorders. The WES was applied to identify the impaired gene in this case and a homozygous missense mutation (c.2348T>C; p.Leu783Pro) in the exon 12 of the GUCY2D gene was detected, followed by heterozygous mutations in her consanguine parents that resulted in homogeneity in their child.
The GUCY2D gene located in chromosome 17, encodes retGC-1 protein that plays a critical role in restoring photoreceptor sensitivity by converting guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) (10). It was declared that GUCY2D gene mutations accounted for about 6–21% of all LCA cases (13). Considering the most of 127-point mutations detected so far in GUCY2D gene can affect all retGC-1 domains and subsequently result in LCA phenotype (9, 13), our finding also added another a novel missense mutation in GUCY2D gene leading to LCA-1 disorder.
We proposed that this novel missense mutation encodes an impaired form of retGC-1 protein that probably defects in function or stability resulting in LCA-1 clinical manifestations. In addition, it has been described previously that the LCA-1 phenotype caused by mutations in the retGC-1, dramatically reduced retGC-1 activity (9, 13). So that, in a study, Xue Feng et al. evaluated a Chinese family with LCA-1 to determine underlying genetic defect and showed that there were 3 novel mutation in the GUCY2D gene result in truncated protein or activity reduction (13). In another investigation, Libe Gradstein et al. described a novel mutation in GUCY2D gene as well as other known mutations in eight affected LCA patients. In addition, molecular modeling approaches implied that loss of retGC-1 helical structure because of the c.2129C>T; p.Ala710Val mutation in the GUCY2D gene, which is likely to affect the catalytic center (14).
Finally, the GUCY2D-p.L783P mutation was identified in an Iranian patient affected by LCA-1 and hasn’t been previously reported in any of the mutation databases. we have four pieces of evidence proves that this mutation can lead to LCA-1: 1- Only this mutation was detected by WES and could be the main cause of LCA-1. 2- Bioinformatics tools such as SIFT, PolyPhen-2 and Mutation taster confirmed that this variant was predicted to be damaging and disease-causing. 3- According to the samples were analyzed by direct Sanger sequencing (Fig. 1B), the presence of this mutation was proved in the patient, and the pattern of inheritance must be an autosomal recessive for the GUCY2D gene because the patient carries a homozygous mutation and her consanguine parents are heterozygous for the detected mutation. 4- A point mutation c.2348T>C of the GUCY2D gene, in exon 12 causes substitution of leucine by proline at position 783 which would be expected to affect retGC-1 function.