A variant in the RP1L1 gene in a family with occult macular dystrophy in a predicted intrinsically disordered region

Abstract

Significance: The responsible genetic variants for occult macular dystrophy (OMD) were found at the predicted intrinsically disordered region (IDR) of the RP1L1 gene. Purpose: We examined the phenotypes and genotypes of family members from OMD. In addition, the genetic characteristics of the RP1L1 gene in OMD were investigated. Methods: Whole-exome sequencing was applied on two affected family members, and Sanger sequencing was performed on three members. The structural property of RP1L1 and pathogenic variants was analyzed using predictor of natural disordered regions (PONDR). Results: Two affected members showed moderate visual impairment and relative central scotoma. The spectral domain optical coherence tomography (SD-OCT) images showed an absence of the interdigitation zone (IZ) and ellipsoid zone (EZ) in one case, and an obscure EZ line in the other case. A RP1L1 variant (c.3593 C > T, p.Ser1198Phe) was identified in two affected members but not in the unaffected member. The PONDR analysis showed that the region from p.1189 to p.1248 could be predicted to be an IDR in the RP1L1 molecule. And the p. Ser1198Phe variant showed significant reduction of PONDR score. Conclusions: Although, the major pathogenic variant of OMD is p.Arg45Trp, multiple reports indicate that the region between p.1194 and p.1201 is another hot spot of OMD. The PONDR analysis predicted that the RP1L1 molecule is one of the intrinsically disordered proteins. It is speculated that the region around p.1200 is essential for the normal function of the RP1L1 molecule, and the missense variants of that area cause the development of OMD.

Assessing the clinical utility of protein structural analysis in genomic variant classification: experiences from a diagnostic laboratory

“…With respect to regions of structural disorder, this property can be assessed by online tools such as IUPRED3 [ 78 ] or GeneSilico MetaDisorder [ 79 ] or by inspection of the MobiDB database [ 80 ] entry for the protein. Variants which alter the propensity for disorder have been implicated in the progression of occult macular dystrophy [ 56 ] and amyotrophic lateral sclerosis [ 57 ]; however, the effects of such variants on protein function will likely be difficult to predict from in silico analysis alone. Conversely, the effects of missense variants on SLiMs and sites of post-translational modification within regions of disorder can be more readily understood, providing utility for tools such as ELM, ScanSite 4.0 and PhosphoSitePlus [ 81 ].…”

Prenatal diagnosis and genetic counseling of a uniparental isodisomy of chromosome 8 with no phenotypic abnormalities

“…We found some cases of paternal UPD8 with phenotypic abnormalities [ 7 ], the nosogenesis of most cases is the homozygote state of recessive pathogenic gene [ 11 – 16 ], but in other cases the cause is unknown [ 17 ]. There are several suspected recessive pathogenic genes for inherited disorders on chromosome 8p23.3p12 such as XKR6 , MIR597 [ 18 ] , RP1L1 [ 19 ] and PPP1R3B [ 20 ]. In our case, no pathogenic mutations or homozygous recessive pathogenic genes were detected by CMA and WES.…”

New recessive compound heterozygous variants of RP1L1 in RP1L1 maculopathy

“…Currently, the presence of p.Arg45Trp variant in RP1L1 is the hot mutation in OMD [22] . Other studies showed that the region between p.1194 and p.1201 is another hot spot of OMD [23] . Based on OCT, patients with OMD can usually be divided into two phenotypic groups, a group with the classical SD-OCT findings in which there was blurring of the EZ and absence of the IZ [24] .…”