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1.
J Transl Med ; 17(1): 351, 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31655630

RESUMO

BACKGROUND: Biallelic PTPRQ pathogenic variants have been previously reported as causative for autosomal recessive non-syndromic hearing loss. In 2018 the first heterozygous PTPRQ variant has been implicated in the development of autosomal dominant non-syndromic hearing loss (ADNSHL) in a German family. The study presented the only, so far known, PTPRQ pathogenic variant (c.6881G>A) in ADNSHL. It is located in the last PTPRQ coding exon and introduces a premature stop codon (p.Trp2294*). METHODS: A five-generation Polish family with ADNSHL was recruited for the study (n = 14). Thorough audiological, neurotological and imaging studies were carried out to precisely define the phenotype. Genomic DNA was isolated from peripheral blood samples or buccal swabs of available family members. Clinical exome sequencing was conducted for the proband. Family segregation analysis of the identified variants was performed using Sanger sequencing. Single nucleotide polymorphism array on DNA samples from the Polish and the original German family was used for genome-wide linkage analysis. RESULTS: Combining clinical exome sequencing and family segregation analysis, we have identified the same (NM_001145026.2:c.6881G>A, NP_001138498.1:p.Trp2294*) PTPRQ alteration in the Polish ADNSHL family. Using genome-wide linkage analysis, we found that the studied family and the original German family derive from a common ancestor. Deep phenotyping of the affected individuals showed that in contrast to the recessive form, the PTPRQ-related ADNSHL is not associated with vestibular dysfunction. In both families ADNSHL was progressive, affected mainly high frequencies and had a variable age of onset. CONCLUSION: Our data provide the first confirmation of PTPRQ involvement in ADNSHL. The finding strongly reinforces the inclusion of PTPRQ to the small set of genes leading to both autosomal recessive and dominant hearing loss.

2.
Invest Ophthalmol Vis Sci ; 60(10): 3388-3397, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31387115

RESUMO

Purpose: To report the clinical and molecular findings in patients with retinal dystrophy associated with the c.783G>A variant in CDHR1. Methods: The retinal phenotype of 10 patients with CDHR1-related retinopathy was characterized by multimodal imaging including color fundus photography, optical coherence tomography (OCT), and blue- and near-infrared fundus autofluorescence imaging. Functional testing included electroretinography, visual acuity, and visual field testing. Results: Six patients homozygous for the c.783G>A variant in CDHR1 showed a retinal phenotype resembling central areolar choroidal dystrophy (CACD) on multimodal imaging. Retinal function outside an area of slowly progressive macular atrophy remained relatively preserved. In contrast, biallelic severe/truncating CDHR1 mutations result in retina-wide retinal degeneration in addition to macular atrophy, with overall severely reduced retinal function. Patients compound heterozygous for the c.783G>A mutation and a truncating mutation in CDHR1 showed an intermediate phenotype. All patients except one with biallelic severe CDHR1 mutations were asymptomatic in the first four decades of life, irrespective of their individual CDHR1 mutations. Analysis of blood RNA from patients with the c.783G>A variant revealed in-frame skipping of exon 8 in vivo, predicting a partial deletion of CDHR1 ectodomains 2 and 3. Conclusions: Patients with biallelic c.783G>A CDHR1 mutations demonstrate a retinal phenotype consistent with autosomal recessive CACD. The apparently silent dbSNP-annotated c.783G>A CDHR1 variant (rs147346345) has a relatively high minor allele frequency (0.31%), with homozygous individuals annotated in the general population, and it may therefore have been disregarded in many next-generation sequencing (NGS)-based studies. The differential diagnosis includes PRPH2-associated CACD and age-related macular degeneration.

3.
FASEB J ; 33(10): 11507-11527, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31345061

RESUMO

We previously reported that inactivation of the transmembrane taurine transporter (TauT or solute carrier 6a6) causes early retinal degeneration in mice. Compatible with taurine's indispensability for cell volume homeostasis, protein stabilization, cytoprotection, antioxidation, and immuno- and neuromodulation, mice develop multisystemic dysfunctions (hearing loss; liver fibrosis; and behavioral, heart, and skeletal muscle abnormalities) later on. Here, by genetic, cell biologic, in vivo 1H-magnetic resonance spectroscopy and molecular dynamics simulation studies, we conducted in-depth characterization of a novel disorder: human TAUT deficiency. Loss of TAUT function due to a homozygous missense mutation caused panretinal degeneration in 2 brothers. TAUTp.A78E still localized in the plasma membrane but is predicted to impact structural stabilization. 3H-taurine uptake by peripheral blood mononuclear cells was reduced by 95%, and taurine levels were severely reduced in plasma, skeletal muscle, and brain. Extraocular dysfunctions were not yet detected, but significantly increased urinary excretion of 8-oxo-7,8-dihydroguanosine indicated generally enhanced (yet clinically unapparent) oxidative stress and RNA oxidation, warranting continuous broad surveillance.-Preising, M. N., Görg, B., Friedburg, C., Qvartskhava, N., Budde, B. S., Bonus, M., Toliat, M. R., Pfleger, C., Altmüller, J., Herebian, D., Beyer, M., Zöllner, H. J., Wittsack, H.-J., Schaper, J., Klee, D., Zechner, U., Nürnberg, P., Schipper, J., Schnitzler, A., Gohlke, H., Lorenz, B., Häussinger, D., Bolz, H. J. Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration.

4.
Clin Exp Ophthalmol ; 47(6): 779-786, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30977268

RESUMO

IMPORTANCE: Uncommon characteristics in genetically unsolved retinitis pigmentosa (RP) patients may indicate an incorrect clinical diagnosis or as yet unknown genetic causes resulting in specific retinal phenotypes. The diagnostic yield of targeted next-generation sequencing may be increased by a reasonable preselection of RP-patients. BACKGROUND: To systematically evaluate and compare features of genetically solved and unsolved RP-patients. DESIGN: Retrospective, observational study. PARTICIPANTS: One-hundred and twelve consecutive RP-patients who underwent extensive molecular genetic analysis. METHODS: Characterization of patients based on multimodal imaging and medical history. MAIN OUTCOME MEASURES: Differences between genetically solved and unsolved RP-patients. RESULTS: Compared to genetically solved patients (n = 77), genetically unsolved patients (n = 35) more frequently had an age of disease-onset above 30 years (60% vs 8%; P < 0.0001), showed atypical fundus features (49% vs 8%; P < 0. 0001) and indicators for phenocopies (eg, autoimmune diseases) (17% vs 0%; P < 0. 001). Evidence for a particular inheritance pattern was less common (20% vs 49%; P < 0. 01). The diagnostic yield was 84% (71/85) in patients with first symptoms below 30 years-of-age, compared to 69% (77/112) in the overall cohort. The other selection criteria alone or in combination resulted in limited further increase of the diagnostic yield (up to 89%) while excluding considerably more patients (up to 56%) from genetic testing. CONCLUSIONS AND RELEVANCE: The medical history and retinal phenotype differ between genetically solved and a subgroup of unsolved RP-patients, which may reflect undetected genotypes or retinal conditions mimicking RP. Patient stratification may inform on the individual likelihood of identifying disease-causing mutations and may impact patient counselling.

5.
PLoS One ; 13(12): e0207958, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30543658

RESUMO

Retinitis pigmentosa (RP) is an inherited degenerative disease causing severe retinal dystrophy and visual impairment mainly with onset in infancy or adolescence. Targeted next-generation sequencing (NGS) has become an efficient tool to encounter the enormous genetic heterogeneity of diverse retinal dystrophies, including RP. To identify disease-causing mutations in unselected, consecutive RP patients, we conducted Sanger sequencing of genes commonly involved in the suspected genetic RP subtype, followed by targeted large-panel NGS if no mutation was identified, or NGS as primary analysis. A high (70%) detection rate of disease-causing mutations was achieved in a large cohort of 116 unrelated patients. About half (48%) of the solved RP cases were explained by mutations in four genes: RPGR, EYS, PRPF31 and USH2A. Overall, 110 different mutations distributed across 30 different genes were detected, and 46 of these mutations were novel. A molecular diagnosis was achieved in the majority (82-100%) of patients if the family history was suggestive for a particular mode of inheritance, but only in 60% in cases of sporadic RP. The diagnostic potential of extensive molecular analysis in a routine setting is also illustrated by the identification of unexpected genotype-phenotype correlations for RP patients with mutations in CRX, CEP290, RPGRIP1, MFSD8. Furthermore, we identified numerous mutations in autosomal dominant (PRPF31, PRPH2, CRX) and X-linked (RPGR) RP genes in patients with sporadic RP. Variants in RP2 and RPGR were also found in female RP patients with apparently sporadic or dominant disease. In summary, this study demonstrates that massively parallel sequencing of all known retinal dystrophy genes is a valuable diagnostic approach for RP patients.


Assuntos
Testes Genéticos/métodos , Retinite Pigmentosa/genética , Adolescente , Adulto , Idoso , Estudos Transversais , Análise Mutacional de DNA/métodos , Feminino , Genes Ligados ao Cromossomo X/genética , Estudos de Associação Genética , Alemanha , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Padrões de Herança/genética , Masculino , Pessoa de Meia-Idade , Mutação , Retinite Pigmentosa/diagnóstico por imagem , Estudos Retrospectivos
7.
JAMA Ophthalmol ; 136(7): 761-769, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29800053

RESUMO

Importance: Co-occurrence of retinitis pigmentosa (RP) and olfactory dysfunction may have a common genetic cause. Objective: To report olfactory function and the retinal phenotype in patients with biallelic mutations in CNGB1, a gene coding for a signal transduction channel subunit expressed in rod photoreceptors and olfactory sensory neurons. Design, Setting, and Participants: This case series was conducted from August 2015 through July 2017. The setting was a multicenter study involving 4 tertiary referral centers for inherited retinal dystrophies. Participants were 9 patients with CNGB1-associated RP. Main Outcomes and Measures: Results of olfactory testing, ocular phenotyping, and molecular genetic testing using targeted next-generation sequencing. Results: Nine patients were included in the study, 3 of whom were female. Their ages ranged between 34 and 79 years. All patients had an early onset of night blindness but were usually not diagnosed as having RP before the fourth decade because of slow retinal degeneration. Retinal features were characteristic of a rod-cone dystrophy. Olfactory testing revealed reduced or absent olfactory function, with all except one patient scoring in the lowest quartile in relation to age-related norms. Brain magnetic resonance imaging and electroencephalography measurements in response to olfactory stimulation were available for 1 patient and revealed no visible olfactory bulbs and reduced responses to odor, respectively. Molecular genetic testing identified 5 novel (c.1312C>T, c.2210G>A, c.2492+1G>A, c.2763C>G, and c.3044_3050delGGAAATC) and 5 previously reported mutations in CNGB1. Conclusions and Relevance: Mutations in CNGB1 may cause an autosomal recessive RP-olfactory dysfunction syndrome characterized by a slow progression of retinal degeneration and variable anosmia or hyposmia.

8.
Sci Rep ; 8(1): 4824, 2018 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-29555955

RESUMO

Macular and cone/cone-rod dystrophies (MD/CCRD) demonstrate a broad genetic and phenotypic heterogeneity, with retinal alterations solely or predominantly involving the central retina. Targeted next-generation sequencing (NGS) is an efficient diagnostic tool for identifying mutations in patient with retinitis pigmentosa, which shows similar genetic heterogeneity. To detect the genetic causes of disease in patients with MD/CCRD, we implemented a two-tier procedure consisting of Sanger sequencing and targeted NGS including genes associated with clinically overlapping conditions. Disease-causing mutations were identified in 74% of 251 consecutive MD/CCRD patients (33% of the variants were novel). Mutations in ABCA4, PRPH2 and BEST1 accounted for 57% of disease cases. Further mutations were identified in CDHR1, GUCY2D, PROM1, CRX, GUCA1A, CERKL, MT-TL1, KIF11, RP1L1, MERTK, RDH5, CDH3, C1QTNF5, CRB1, JAG1, DRAM2, POC1B, NPHP1 and RPGR. We provide detailed illustrations of rare phenotypes, including autofluorescence and optical coherence tomography imaging. Targeted NGS also identified six potential novel genotype-phenotype correlations for FAM161A, INPP5E, MERTK, FBLN5, SEMA4A and IMPDH1. Clinical reassessment of genetically unsolved patients revealed subgroups with similar retinal phenotype, indicating a common molecular disease cause in each subgroup.

9.
Front Genet ; 8: 130, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29018476

RESUMO

In an Egyptian girl born to consanguineous parents, whole-exome sequencing (WES) identified a homozygous mutation in PHGDH, c.1273G>A (p.Val425Met), indicating 3-phosphoglycerate dehydrogenase deficiency. This diagnosis was compatible with the patient's microcephaly, severe psychomotor retardation, seizures and cataracts. However, she additionally suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization, suggesting a secondary, predisposing and potentially Mendelian, condition. A local reactivation of an EBV infection in the respiratory tract was detected after a recent chest infection, likely representing an opportunistic infection based on a compromised immune system. Further inspection of WES data revealed a homozygous nonsense mutation, c.2665A>T (p.Lys889∗), in IFIH1, encoding MDA5. MDA5 detects long viral double-stranded RNA that is generated during replication of picorna viruses, and thereby activates the type I interferon signaling pathway. The results of Western blot analysis of protein from cultured fibroblasts of the patient indicates absence of wild type MDA5/IFIH1, compatible with NMD. We propose that, analogous to the severe course of primary influenza infection due to biallelic deficiency of a downstream effector, IRF7, homozygous loss of IFIH1 defines a novel Mendelian immunodeficiency disorder that increases susceptibility to severe viral infections. This is contrasted to heterozygous gain-of-function IFIH1 mutations in autoimmune diseases. Our findings highlight the potential of comprehensive genomic investigations in patients from consanguineous families to identify monogenic predispositions to severe infections.

10.
Mol Genet Genomic Med ; 5(5): 531-552, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28944237

RESUMO

BACKGROUND: Combined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP). METHODS: Sanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array-CGH were conducted in 138 patients clinically diagnosed with Usher syndrome. RESULTS: A molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array-CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified USH2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC124-induced read-through of the common p.Trp3955* nonsense mutation (13% of detected USH2A alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in OTOA and NR2E3, genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, for the first time linking this gene to Heimler syndrome. CONCLUSION: Targeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.

11.
Invest Ophthalmol Vis Sci ; 58(10): 3950-3959, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28785766

RESUMO

Purpose: This study sought to characterize the ophthalmic and extraocular phenotype in patients with known and novel KIF11 mutations. Methods: Four patients (3, 5, 36, and 38 years of age, on father-daughter constellation) from three unrelated families were characterized by retinal examination including multimodal retinal imaging, investigation for syndromic disease manifestations, and targeted next-generation sequencing. The subcellular localization of Kif11 in the retina was analyzed by light and electron microcopy. Results: There was considerable interindividual and intrafamilial phenotypic heterogeneity of KIF11-related retinopathy. Two patients presented with a progressive retinal dystrophy, one with chorioretinal dysplasia and one with familial exudative vitreoretinopathy (FEVR) in one eye and thinning of the photoreceptor layer in the fellow eye. Obvious syndromic disease manifestations were present only in the youngest patient, but minor signs (e.g. reduced head circumference) were present in the three other individuals. Immunohistochemistry results demonstrated Kif11 localization in the inner segment and ciliary compartments of photoreceptor cells and in the retinal pigment epithelium. Conclusions: Progressive retinal degeneration in KIF11-related retinopathy indicates a role for KIF11 not only in ocular development but also in maintaining retinal morphology and function. The remarkable variability of the ocular phenotype suggests four different types of retinopathy which may overlap. KIF11 should be considered in the screening of patients with retinal dystrophies because other syndromic manifestations may be subtle. Evaluation of head circumference may be considered as a potential shortcut to the genetic diagnosis. The localization of Kif11 in photoreceptor cells indicates a retinal ciliopathy.


Assuntos
Cinesina/genética , Mutação , Distrofias Retinianas/genética , Adulto , Animais , Western Blotting , Pré-Escolar , Análise Mutacional de DNA , Eletrorretinografia , Feminino , Angiofluoresceinografia , Aconselhamento Genético , Humanos , Cinesina/metabolismo , Masculino , Camundongos , Imagem Multimodal , Imagem Óptica , Linhagem , Fenótipo , Células Fotorreceptoras de Vertebrados/metabolismo , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/metabolismo , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia
12.
Sci Rep ; 7(1): 1411, 2017 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-28469144

RESUMO

Deafblindness is mostly due to Usher syndrome caused by recessive mutations in the known genes. Mutation-negative patients therefore either have distinct diseases, mutations in yet unknown Usher genes or in extra-exonic parts of the known genes - to date a largely unexplored possibility. In a consanguineous Saudi family segregating Usher syndrome type 1 (USH1), NGS of genes for Usher syndrome, deafness and retinal dystrophy and subsequent whole-exome sequencing each failed to identify a mutation. Genome-wide linkage analysis revealed two small candidate regions on chromosome 3, one containing the USH3A gene CLRN1, which has never been associated with Usher syndrome in Saudi Arabia. Whole-genome sequencing (WGS) identified a homozygous deep intronic mutation, c.254-649T > G, predicted to generate a novel donor splice site. CLRN1 minigene-based analysis confirmed the splicing of an aberrant exon due to usage of this novel motif, resulting in a frameshift and a premature termination codon. We identified this mutation in an additional two of seven unrelated mutation-negative Saudi USH1 patients. Locus-specific markers indicated that c.254-649T > G CLRN1 represents a founder allele that may significantly contribute to deafblindness in this population. Our finding underlines the potential of WGS to uncover atypically localized, hidden mutations in patients who lack exonic mutations in the known disease genes.

13.
Ophthalmic Genet ; 38(4): 380-382, 2017 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27668459

RESUMO

PURPOSE: To document recessive FZD4-related familial exudative vitreoretinopathy. METHODS: Retrospective case series. RESULTS: Two brothers, the only two males among five siblings, had bilateral infantile retinal detachments and were referred for genetic counseling. Next-generation sequencing uncovered a homozygous FZD4 frameshift deletion in both affected brothers (c.40_49delCCCGGGGGCG; p.Pro14Serfs*44). None of the other immediate family members had clinical evidence for retinal disease, including the three family members who underwent confirmatory genetic testing and were found to be heterozygous for the mutation (both parents and one sister). CONCLUSIONS: The findings in this family support the concept that some mutated FZD4 alleles can be associated with recessive rather than dominant disease.


Assuntos
Mutação da Fase de Leitura , Receptores Frizzled/genética , Doenças Retinianas/genética , Deleção de Sequência , Consanguinidade , Oftalmopatias Hereditárias , Angiofluoresceinografia , Genes Recessivos , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Masculino , Linhagem , Reação em Cadeia da Polimerase , Doenças Retinianas/diagnóstico , Estudos Retrospectivos , Irmãos
14.
Ophthalmic Genet ; 37(3): 301-6, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26885695

RESUMO

PURPOSE: Recessive mutations in CDH3 cause "hypotrichosis with juvenile macular dystrophy," typically recognized by the presence of prominent dermatological features. We report novel phenotypic observations and associated mutations in four patients from three families, including one who did not have frank hypotrichosis. METHODS: Retrospective case series (2010-2014). RESULTS: Four affected individuals from three consanguineous Arabian families were identified. All four subjects (two sisters and two unrelated males; 5, 13, 17, and 26 years old) had homozygous recessive CDH3 mutations not previously associated with the condition (c.307C>T; p.R103 in two sisters, c.1859_1862delCTCT in both unrelated males). Symptomatic visual loss was since birth or early childhood. One male subject did not have frank hypotrichosis, but review of symptoms revealed relatively slow hair growth and an inability to conceive children. None had dental or digital findings, although one female noted slow nail growth. All had a circumscribed central maculopathy with borders that did not respect posterior pole horizontal arterioles (typically extending beyond the major arcades) and associated with polygonal pigment clumping. Recognition of this pattern led us to suspect the diagnosis in the male without frank hypotrichosis. Retinal dysfunction was cone-rod (rather than macular only) by ERG in one patient, who developed severe central macular atrophy and a macular hole. CONCLUSIONS: Ophthalmologists should consider the diagnosis of CDH3-related retinopathy in individuals with such clinical features whether or not there is frank hypotrichosis.


Assuntos
Caderinas/genética , Hipotricose/genética , Degeneração Macular/genética , Mutação , Adolescente , Adulto , Pré-Escolar , Consanguinidade , Feminino , Genes Recessivos , Homozigoto , Humanos , Hipotricose/diagnóstico , Degeneração Macular/diagnóstico , Masculino , Linhagem , Fenótipo , Estudos Retrospectivos , Análise de Sequência de DNA
15.
Ophthalmic Genet ; 37(3): 290-3, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26854863

RESUMO

Bardet-Biedl syndrome (BBS) is a pleiotropic and clinically and genetically heterogeneous ciliopathy. Primary features are early-onset retinal dystrophy that is typically rod-cone, obesity, polydactyly, renal abnormalities, hypogonadism, and learning difficulties, but most patients do not present with the full clinical picture. In a BBS patient from a consanguineous marriage we performed next-generation sequencing targeting all known BBS genes and other genes known or hypothesized to cause ciliopathies. While no mutation was present in any of the recognized genes for BBS, we were able to identify the homozygous non-conservative mutation c.529C>T (p.Arg177Trp) in C8orf37 that segregated with the phenotype, affects an evolutionarily highly conserved residue, and is bioinformatically predicted to be pathogenic. The same mutation has been described in unrelated patients with non-syndromic cone-rod dystrophy and other C8orf37 changes were found in individuals with retinitis pigmentosa. We conclude that C8orf37 should be added to BBS screening panels as a probable rare cause of the disease and that individuals with C8orf37-related retinal dystrophy should be screened for BBS features.


Assuntos
Síndrome de Bardet-Biedl/genética , Mutação , Proteínas/genética , Distrofias Retinianas/genética , Alelos , Síndrome de Bardet-Biedl/diagnóstico , Criança , Consanguinidade , Análise Mutacional de DNA , Genes Recessivos , Humanos , Masculino , Fenótipo , Distrofias Retinianas/diagnóstico
16.
Br J Ophthalmol ; 100(6): 829-33, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26359340

RESUMO

BACKGROUND: Conorenal syndrome is a systemic skeletal ciliopathy characterised by skeletal and renal findings and caused by biallelic mutations in the gene intraflagellar transport 140 Chlamydomonas homologue (IFT140). Most studies have focused on syndromic features and are by non-ophthalmologists. We highlight the ophthalmic phenotype. METHODS: Retrospective consecutive case series (2010-2014). RESULTS: Twelve subjects with confirmed homozygous mutations were identified (11 consanguineous families; 7 boys; assessed at age 10 months to 20 years, average and median age 6.5 and 4 years). All were homozygous for the same IFT140 mutation (c.1990G>A; p.Glu664Lys) except one who was homozygous for c.1541_1542delinsAA. All had poor vision and nystagmus since birth, with visual acuity after 5 years old of hand motions or light perception. In early childhood, nine were noted to stare at lights, four were noted to have a happy demeanour, high hyperopia was typical, and electroretinography was non-recordable. Fundus appearance was grossly normal before the age of 1 year but thereafter appeared dystrophic. Eight children had developmental delay, two had short stubby fingers, and one had renal disease, but four had no evident extraocular disease, including one aged 18 years who also had two older affected siblings in their twenties who remained non-syndromic and were excelling academically. CONCLUSIONS: Recessive IFT140 mutations cause a severe congenital retinal dystrophy with high hyperopia and often early photophilia. Developmental delay is common but not universal and not all patients have obvious extraocular findings. The c.1990G>A mutation represents a founder effect or mutational hotspot on the Arabian Peninsula.


Assuntos
Proteínas de Transporte/genética , Ciliopatias/genética , DNA/genética , Mutação , Distrofias Retinianas/congênito , Adolescente , Proteínas de Transporte/metabolismo , Criança , Pré-Escolar , Ciliopatias/etiologia , Ciliopatias/metabolismo , Análise Mutacional de DNA , Eletrorretinografia , Feminino , Genes Recessivos , Homozigoto , Humanos , Lactente , Masculino , Linhagem , Fenótipo , Retina/diagnóstico por imagem , Retina/fisiopatologia , Distrofias Retinianas/complicações , Distrofias Retinianas/genética , Estudos Retrospectivos , Adulto Jovem
17.
Br J Ophthalmol ; 100(2): 209-15, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26061163

RESUMO

BACKGROUND: Dominant mutations in peripherin (PRPH2) are associated with a spectrum of retinal dystrophy phenotypes, many of which are adult onset and involve the macula. Recessive PRPH2 mutations cause retinal dystrophy associated with prominent maculopathy in adulthood; however, the presenting childhood phenotype has not been defined. We characterise this phenotype. METHODS: Retrospective case series of families harbouring bi-allelic PRPH2 mutations (2010-2014). RESULTS: Three children (two families; assessed at 2 years old) and two adults (one family; assessed at 24 and 35 years old) with homozygous PRPH2 mutations (c.497G>A (p.Cys166Tyr) or c.136C>T (p.Arg46*)) all had infantile nystagmus and decreased vision noted soon after birth and a history of staring at lights during infancy (photophilia). The three children had high hyperopia, a normal or near normal fundus, and non-recordable electroretinographies (ERGs). The two adults had slight myopia, macular and peripheral retinal changes, and non-recordable ERGs. All five available carrier parents had macular±peripheral retinal findings, although they considered themselves asymptomatic except for one mother who had developed visual loss in one eye at 48 years old and had an associated subfoveal lesion. CONCLUSIONS: Bi-allelic PRPH2 mutations cause a distinct Leber congenital amaurosis phenotype in infancy; affected adults have prominent maculopathy. Heterozygous parents can be asymptomatic but have clinically obvious macular phenotypes with or without peripheral retinal findings, which can be helpful in making the genetic diagnosis in affected children. The difference between the heterozygous and homozygous phenotypes is likely related to gene product dosage effect.


Assuntos
Genes Recessivos/genética , Amaurose Congênita de Leber/genética , Mutação , Periferinas/genética , Adulto , Alelos , Eletrorretinografia , Feminino , Heterozigoto , Humanos , Lactente , Amaurose Congênita de Leber/diagnóstico , Amaurose Congênita de Leber/fisiopatologia , Masculino , Nistagmo Patológico/diagnóstico , Nistagmo Patológico/genética , Nistagmo Patológico/fisiopatologia , Pais , Linhagem , Fenótipo , Retina/fisiopatologia , Doenças Retinianas/diagnóstico , Doenças Retinianas/genética , Doenças Retinianas/fisiopatologia , Estudos Retrospectivos , Campos Visuais/fisiologia , Adulto Jovem
18.
Hum Mutat ; 37(2): 170-4, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26593283

RESUMO

Deafblindness is part of several genetic disorders. We investigated a consanguineous Egyptian family with two siblings affected by congenital hearing loss and retinal degeneration, initially diagnosed as Usher syndrome type 1. At teenage, severe enamel dysplasia, developmental delay, and microcephaly became apparent. Genome-wide homozygosity mapping and whole-exome sequencing detected a homozygous missense mutation, c.1238G>T (p.Gly413Val), affecting a highly conserved residue of peroxisomal biogenesis factor 6, PEX6. Biochemical profiling of the siblings revealed abnormal and borderline plasma phytanic acid concentration, and cerebral imaging revealed white matter disease in both. We show that Pex6 localizes to the apical extensions of secretory ameloblasts and differentiated odontoblasts at early stages of dentin synthesis in mice, and to cilia of retinal photoreceptor cells. We propose PEX6, and possibly other peroxisomal genes, as candidate for the rare cooccurrence of deafblindness and enamel dysplasia. Our study for the first time links peroxisome biogenesis disorders to retinal ciliopathies.


Assuntos
Adenosina Trifosfatases/genética , Transtornos da Surdocegueira/genética , Hipoplasia do Esmalte Dentário/genética , Microcefalia/genética , Mutação de Sentido Incorreto , Degeneração Retiniana/genética , ATPases Associadas a Diversas Atividades Celulares , Adenosina Trifosfatases/metabolismo , Ameloblastos/metabolismo , Ameloblastos/patologia , Sequência de Aminoácidos , Animais , Criança , Cílios/metabolismo , Cílios/patologia , Consanguinidade , Transtornos da Surdocegueira/metabolismo , Transtornos da Surdocegueira/patologia , Hipoplasia do Esmalte Dentário/metabolismo , Hipoplasia do Esmalte Dentário/patologia , Feminino , Expressão Gênica , Homozigoto , Humanos , Masculino , Camundongos , Microcefalia/metabolismo , Microcefalia/patologia , Dados de Sequência Molecular , Odontoblastos/metabolismo , Odontoblastos/patologia , Linhagem , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/patologia , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Irmãos , Substância Branca/metabolismo , Substância Branca/patologia , Adulto Jovem
19.
Elife ; 42015 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-26386247

RESUMO

Joubert syndrome (JBTS) is a severe recessive neurodevelopmental ciliopathy which can affect several organ systems. Mutations in known JBTS genes account for approximately half of the cases. By homozygosity mapping and whole-exome sequencing, we identified a novel locus, JBTS23, with a homozygous splice site mutation in KIAA0586 (alias TALPID3), a known lethal ciliopathy locus in model organisms. Truncating KIAA0586 mutations were identified in two additional patients with JBTS. One mutation, c.428delG (p.Arg143Lysfs*4), is unexpectedly common in the general population and may be a major contributor to JBTS. We demonstrate KIAA0586 protein localization at the basal body in human and mouse photoreceptors, as is common for JBTS proteins, and also in pericentriolar locations. We show that loss of TALPID3 (KIAA0586) function in animal models causes abnormal tissue polarity, centrosome length and orientation, and centriolar satellites. We propose that JBTS and other ciliopathies may in part result from cell polarity defects.


Assuntos
Proteínas de Ciclo Celular/genética , Polaridade Celular , Centrossomo/metabolismo , Cerebelo/anormalidades , Mutação , Retina/anormalidades , Anormalidades Múltiplas/genética , Animais , Modelos Animais de Doenças , Anormalidades do Olho/genética , Humanos , Doenças Renais Císticas/genética , Camundongos
20.
Br J Ophthalmol ; 99(12): 1725-31, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26294103

RESUMO

BACKGROUND/AIM: We have noted a phenotype of early-onset retinal dystrophy with macular staphyloma but without high myopia. The aim of this study is to report the underlying genetic mutations and the subcellular localisation of the gene product in the retina. METHODS: Retrospective case series (2012-2015); immunohistochemical analyses of mammalian retina for in situ protein localisation. RESULTS: All three probands were first noted to have decreased vision at 3-6 years old which worsened over time. At ages 39, 37 and 12 years old, all had similar retinal findings: dystrophic changes (retinal pigment epithelium mottling, vessel narrowing), macular staphyloma (despite only mild myopia or high hyperopia), and non-recordable electroretinography. All harboured homozygous mutations in C21orf2, a gene recently suggested to be associated with retinal dystrophy but of unknown function. Two had a frameshift deletion c.436_466del (p.Glu146Serfs*6). The third had a missense mutation affecting a highly conserved residue (p.Cys61Tyr) and was short (below the 3rd percentile) and obese (50th percentile for weight despite short stature). Immunohistochemical studies in human, pig and mouse retinas localised C21orf2 protein to the ciliary structures of the photoreceptor cell (the daughter basal body, the centriole adjacent to the basal body, and the connecting cilium). CONCLUSIONS: This retinal dystrophy phenotype is caused by recessive mutations in C21orf2 and can be considered a retinal ciliopathy as C21orf2 encodes a protein that localises to photoreceptor ciliary structures. The short stature and obesity noted in the youngest girl suggest that for some patients biallelic C21orf2 mutations may result in syndromic ciliopathy.


Assuntos
Mutação da Fase de Leitura/genética , Genes Recessivos , Mutação de Sentido Incorreto/genética , Cílio Conector dos Fotorreceptores/metabolismo , Proteínas/genética , Retina/patologia , Distrofias Retinianas/genética , Adulto , Sequência de Aminoácidos , Animais , Western Blotting , Criança , Consanguinidade , Dilatação Patológica , Eletrorretinografia , Feminino , Humanos , Imagem por Ressonância Magnética , Camundongos , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase , Proteínas/metabolismo , Estudos Retrospectivos , Sus scrofa , Doadores de Tecidos , Tomografia de Coerência Óptica
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