Severe manifestations in carrier females in X linked retinitis pigmentosa.

Souied, Eric H.; Segues, Bertrand; Ghazi, Imad; Rozet, Jean–Michel; Châtelin, Sophie; Gerber, Sylvie; Perrault, Isabelle; Michel-Awad, A; Briard, Marie-Louise; Plessis, Ghislaine; Dufier, Jean‐Louis; Münnich, Arnold; Kaplan, Josseline

doi:10.1136/jmg.34.10.793

Cited by 32 publications

(32 citation statements)

References 12 publications

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“…The wide clinical spectrum of RP observed among the female carriers in the families we described could be explained by allelic heterogeneity or a skewed X-inactivation, as noted at RP2 locus [Friedrich et al, 1993], although we did not perform an X-inactivation study. Souied et al [1997] did not observe any preferential patterns of X inactivation in circulating leukocytes of RP3 carrier females with severe manifestation.…”

Section: Discussionmentioning

confidence: 55%

Three novel mutations of theRPGR gene exon ORF15 in three Japanese families with X-linked retinitis pigmentosa

et al. 2001

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We describe three new mutations in a recently identified exon, ORF15, of the retinitis pigmentosa GTPase regulator gene (RPGR) in three unrelated Japanese families (Families 1-3) with X-linked retinitis pigmentosa (XLRP). The affected males had typical retinitis pigmentosa (RP), whereas the obligate carrier females showed a wide clinical spectrum, ranging from minor symptoms to severe visual disability. Some carrier females in Families 1 and 2 showed typical RP, most carriers manifested high myopia and astigmatism, and their corrected visual acuity was insufficient. They showed an impairment of cone function following the rod dysfunction and accompanied by refractive errors. Microsatellite analysis of Family 1 revealed that the RP in the family was linked to the RP3 locus. Although one patient in the family had no mutation in the previously published exons 1-19 including exon 15a, he had a single-nucleotide insertion in exon ORF15 (g.ORF15 + 753-754 insG). Likewise, patients in Families 2 and 3 had two-base insertion/deletion in the exon, i.e., g.ORF15 + 833-834delGG and g.ORF15 + 861-862insGG, respectively. These insertional/deletional mutations observed in the three families are all different and new, and are predicted to lead to a frameshift, resulting in a truncated protein. These findings may support the previous hypothesis that RPGR-ORF15 is a mutational hot spot.

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Section: Discussionmentioning

confidence: 55%

Three novel mutations of theRPGR gene exon ORF15 in three Japanese families with X-linked retinitis pigmentosa

et al. 2001

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“…Although XLRP is thought to affect male subjects only, many documented cases of RPGR and RP2 mutations cause disease in carrier female subjects, thus giving an impression of occurrence in sequential generations simulating Mendelian dominant transmission. [10][11][12][13][14][15] Historically, RPGR carrier female subjects were thought to have much milder (if any) symptoms compared to male subjects with comparable RPGR mutations. 12,15 More recently, it has been reported that carrier female subjects exhibit a range of phenotypes that can vary from asymptomatic to severe retinal disease similar to male subjects.…”

mentioning

confidence: 99%

“…[10][11][12][13][14][15] Historically, RPGR carrier female subjects were thought to have much milder (if any) symptoms compared to male subjects with comparable RPGR mutations. 12,15 More recently, it has been reported that carrier female subjects exhibit a range of phenotypes that can vary from asymptomatic to severe retinal disease similar to male subjects. 10,12,13 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.…”

mentioning

confidence: 99%

Mutations in the X-Linked Retinitis Pigmentosa GenesRPGRandRP2Found in 8.5% of Families with a Provisional Diagnosis of Autosomal Dominant Retinitis Pigmentosa

Churchill

Bowne

Sullivan

et al. 2013

Invest. Ophthalmol. Vis. Sci.

117

124

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PURPOSE. We determined the fraction of families in a wellcharacterized cohort with a provisional diagnosis of autosomal dominant retinitis pigmentosa (adRP) that have disease-causing mutations in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene or the retinitis pigmentosa 2 (RP2) gene. METHODS.Families with a provisional clinical diagnosis of adRP, and a pedigree consistent with adRP but no male-to-male transmission were selected from a cohort of 258 families, and tested for mutations in the RPGR and RP2 genes with di-deoxy sequencing. To facilitate testing of RPGR in ''adRP'' families that had no male members available for testing, the repetitive and purine-rich ORF15 of RPGR was subcloned and sequenced in heterozygous female subjects from 16 unrelated families.RESULTS. Direct sequencing of RPGR and RP2 allowed for identification of a disease-causing mutation in 21 families. Of these ''adRP'' families 19 had RPGR mutations, and two had RP2 mutations. Subcloning and sequencing of ORF15 of RPGR in female subjects identified one additional RPGR mutation. Of the 22 mutations identified, 15 have been reported previously.CONCLUSIONS. These data show that 8.5% (22 in 258) of families thought to have adRP truly have X-linked retinitis pigmentosa (XLRP). These results have substantive implications for calculation of recurrence risk, genetic counseling, and potential treatment options, and illustrate the importance of screening families with a provisional diagnosis of autosomal inheritance and no male-to-male transmission for mutations in X-linked genes. Mutations in RPGR are one of the most common causes of all forms of retinitis pigmentosa. (Invest Ophthalmol Vis Sci.

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“…Therefore the authors regarded this condition as partially X-linked dominant. 101 However, given our more recent understanding of molecular genetics mentioned above, there remains the question of whether this was truly X-linked dominant disease or simply an X-linked condition with more variable expressivity in females as compared to the affected males within a family. Wu et al described a family with X-linked dominant RP.…”

Section: Benign Prostatic Hypertrophy and Prostate Cancermentioning

confidence: 96%

“…The study involved 97 subjects: 28 affected males, 34 affected females, 24 disease free individuals, and 10 subjects with unknown status. 101 All family members underwent extensive testing including anterior and posterior segment examinations, visual acuity testing, Goldmann perimetry, color testing, and ERG testing. Interestingly, the individuals in these families had a delay in disease onset until their second decade of life and their central vision was preserved until 40-45 years of age.…”

Section: Benign Prostatic Hypertrophy and Prostate Cancermentioning

confidence: 99%

Gender Specific Issues in Hereditary Ocular Disorders

Iragavarapu¹,

Gorin²

2014

Current Eye Research

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This review is intended to summarize the current knowledge from basic science and clinical medical literature cited within PubMed that pertain to gender-related factors and affect those individuals with hereditary ocular disorders. We consider gender-related biological factors that (a) affect disease onset and progression, (b) gender differences for major X-linked ocular disorders, (c) gender-specific conditions, (d) medications that may influence genetic eye disorders, and finally, (e) gender-related issues that influence the management and quality of life of these patients. Several studies have demonstrated the manner in which sex-related hormones in animal models are capable of influencing cell pathway and survival that are likely to affect hereditary eye disorders. There are very few clinical studies that provide compelling evidence for gender differences in human ocular conditions, other than for a number of X-linked disorders. Disease expression for X-linked disorders may be impacted by genetic mechanisms such as lyonization or uniparental disomy. Clinical evidence regarding the impact of gender-related medical conditions and therapies on eye conditions is extremely limited and primarily based on anecdotal evidence. Gender-specific factors may play a major role in the underlying biological pathways that influence the onset, rate of progression, and clinical findings associated with ocular genetic conditions. Clinicians need to be aware of the variable phenotypes observed in female carriers of X-linked disorders of gender specific issues, many of which are inadequately addressed in the current literature. Clinicians need to be sensitive to gender differences in social, cultural, and religious systems and they should also be aware of how their own gender biases may influence how they counsel patients. Finally, it is clear that the lack of effective clinical studies in this area creates an opportunity for future research that will have real benefits for these patients.

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Severe manifestations in carrier females in X linked retinitis pigmentosa.

Cited by 32 publications

References 12 publications

Three novel mutations of theRPGR gene exon ORF15 in three Japanese families with X-linked retinitis pigmentosa

Three novel mutations of theRPGR gene exon ORF15 in three Japanese families with X-linked retinitis pigmentosa

Mutations in the X-Linked Retinitis Pigmentosa GenesRPGRandRP2Found in 8.5% of Families with a Provisional Diagnosis of Autosomal Dominant Retinitis Pigmentosa

Gender Specific Issues in Hereditary Ocular Disorders

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