Remapping of the RP15 Locus for X-Linked Cone-Rod Degeneration to Xp11.4-p21.1, and Identification of a De Novo Insertion in the RPGR Exon ORF15

Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 11/2000; 67(4):1000-3. DOI: 10.1086/303091
Source: PubMed


X-linked forms of retinitis pigmentosa (XLRP) are among the most severe, because of their early onset, often leading to significant vision loss before the 4th decade. Previously, the RP15 locus was assigned to Xp22, by linkage analysis of a single pedigree with "X-linked dominant cone-rod degeneration." After clinical reevaluation of a female in this pedigree identified her as affected, we remapped the disease to a 19.5-cM interval (DXS1219-DXS993) at Xp11.4-p21.1. This new interval overlapped both RP3 (RPGR) and COD1. Sequencing of the previously published exons of RPGR revealed no mutations, but a de novo insertion was detected in the new RPGR exon, ORF15. The identification of an RPGR mutation in a family with a severe form of cone and rod degeneration suggests that RPGR mutations may encompass a broader phenotypic spectrum than has previously been recognized in "typical" retinitis pigmentosa.

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Available from: Beverly M Yashar, Mar 12, 2014
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    • "Although XLRP is thought to affect male subjects only, many documented cases of RPGR cause disease in carrier female subjects, which giving an impression of occurrence in sequential generations simulating Mendelian dominant transmission [6]. It has been reported that RPGR carrier female subjects exhibit a range of phenotypes that can vary from asymptomatic to severe retinal disease similar to male subjects [8]–[10]. The presence of “affected” or, at least, partially manifesting female subjects with an absence of male-to-male transmission in a pedigree may lead to misinterpretation [6], which makes the genetic diagnosis difficult and complex. "
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    ABSTRACT: X-linked Retinitis Pigmentosa (XLRP) accounts for 10-20% of all RP cases, and represents the most severe subtype of this disease. Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the most common causes of XLRP, accounting for over 70-75% of all XLRP cases. In this work, we analyzed all the exons of RPGR gene with Sanger sequencing in seven Chinese XLRP families, two of these with a provisional diagnosis of adRP but without male-to-male transmission. Three novel deletions (c.2233_34delAG; c.2236_37delGA and c.2403_04delAG) and two known nonsense mutations (c.851C→G and c.2260G→T) were identified in five families. Two novel deletions (c.2233_34delAG and c.2236_37delGA) resulted in the same frame shift (p.E746RfsX22), created similar phenotype in Family 3 and 4. The novel deletion (c.2403_04delAG; p.E802GfsX31) resulted in both XLRP and x-linked cone-rod dystrophy within the male patients of family 5, which suggested the presence of either genetic or environmental modifiers, or both, play a substantial role in disease expression. Genotype-phenotype correlation analysis suggested that (1) both patients and female carriers with mutation in Exon 8 (Family 1) manifest more severe disease than did those with ORF15 mutations (Family 2&3&4); (2) mutation close to downstream of ORF15 (Family 5) demonstrate the early preferential loss of cone function with moderate loss of rod function.
    PLoS ONE 01/2014; 9(1):e85752. DOI:10.1371/journal.pone.0085752 · 3.23 Impact Factor
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    • "In contrast, dominant inheritance was reported for a couple of RPGR mutations [43,46]. Furthermore, ORF15 mutations have also been associated with phenotypes of the central part of the retina, including cone-rod or cone dystrophies and atrophic macular degeneration [19-21,42]. Consequently, in XLRP cases with manifestations of the phenotype in females or in patients with X-linked cone-dominated retinopathies, we recommend screening exon ORF15 first, followed by the other exons of RPGR. "
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    ABSTRACT: The goal of this study was to identify mutations in X-chromosomal genes associated with retinitis pigmentosa (RP) in patients from Germany, The Netherlands, Denmark, and Switzerland. In addition to all coding exons of RP2, exons 1 through 15, 9a, ORF15, 15a and 15b of RPGR were screened for mutations. PCR products were amplified from genomic DNA extracted from blood samples and analyzed by direct sequencing. In one family with apparently dominant inheritance of RP, linkage analysis identified an interval on the X chromosome containing RPGR, and mutation screening revealed a pathogenic variant in this gene. Patients of this family were examined clinically and by X-inactivation studies. This study included 141 RP families with possible X-chromosomal inheritance. In total, we identified 46 families with pathogenic sequence alterations in RPGR and RP2, of which 17 mutations have not been described previously. Two of the novel mutations represent the most 3'-terminal pathogenic sequence variants in RPGR and RP2 reported to date. In exon ORF15 of RPGR, we found eight novel and 14 known mutations. All lead to a disruption of open reading frame. Of the families with suggested X-chromosomal inheritance, 35% showed mutations in ORF15. In addition, we found five novel mutations in other exons of RPGR and four in RP2. Deletions in ORF15 of RPGR were identified in three families in which female carriers showed variable manifestation of the phenotype. Furthermore, an ORF15 mutation was found in an RP patient who additionally carries a 6.4 kbp deletion downstream of the coding region of exon ORF15. We did not identify mutations in 39 sporadic male cases from Switzerland. RPGR mutations were confirmed to be the most frequent cause of RP in families with an X-chromosomal inheritance pattern. We propose a screening strategy to provide molecular diagnostics in these families.
    Molecular vision 02/2008; 14:1081-93. · 1.99 Impact Factor
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    • "RPGR ORF15 exon mutations account for 30 to 60% of RXLRP and mutations in other RPGR exons account for 11 to 26% of RXLRP [Hardcastle et al., 1999; Mears et al., 1999; Vervoort et al., 2000; Breuer et al., 2002; Sharon et al., 2003]. In addition to RXLRP, RPGR mutations have been described in families segregating RP in both males and females [Rozet et al., 2002], X-linked recessive atrophic macular degeneration or cone degeneration [Ayyagari et al., 2002], X-linked cone-rod dystrophy [Mears et al., 2000; Demirci et al., 2002; Ebenezer et al., 2005], RP and Coats'-like exudative vasculopathy [Demirci et al., 2006], or even RP associated with extraocular ciliary disorders, including recurrent respiratory infections [Iannaccone et al., 2003], deafness, sinorespiratory infections [Zito et al., 2003], and primary ciliary dyskinesia [Moore et al., 2006]. "
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    ABSTRACT: X-linked forms of retinitis pigmentosa (RP) (XLRP) account for 10 to 20% of families with RP and are mainly accounted for by mutations in the RP2 or RP GTPase regulator (RPGR) genes. We report the screening of these genes in a cohort of 127 French family comprising: 1) 93 familial cases of RP suggesting X-linked inheritance, including 48 out of 93 families with expression in females but no male to male transmission; 2) seven male sibships of RP; 3) 25 sporadic male cases of RP; and 4) two cone dystrophies (COD). A total of 5 out of the 93 RP families excluded linkage to the RP2 and RP3 loci and were removed form the cohort. A total of 14 RP2 mutations, 12 of which are novel, were identified in 14 out of 88 familial cases of RP and 1 out of 25 sporadic male case (4%). In 13 out of 14 of the familial cases, no expression of the disease was noted in females, while in 1 out of 14 families one woman developed RP in the third decade. A total of 42 RPGR mutations, 26 of which were novel, were identified in 80 families, including: 69 out of 88 familial cases (78.4%); 2 out of 7 male sibship (28.6%); 8 out of 25 sporadic male cases (32.0%); and 1 out of 2 COD. No expression of the disease was noted in females in 41 out of 69 familial cases (59.4%), while at least one severely affected woman was recognized in 28 out of 69 families (40.6%). The frequency of RP2 and RPGR mutations in familial cases of RP suggestive of X-linked transmission are in accordance to that reported elsewhere (RP2: 15.9% vs. 6-20%; RPGR: 78.4% vs. 55-90%). Interestingly, about 30% of male sporadic cases and 30% of male sibships of RP carried RP2 or RPGR mutations, confirming the pertinence of the genetic screening of XLRP genes in male patients affected with RP commencing in the first decade and leading to profound visual impairment before the age of 30 years.
    Human Mutation 01/2007; 28(1):81-91. DOI:10.1002/humu.20417 · 5.14 Impact Factor
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