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1.
Int J Mol Sci ; 25(11)2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38892339

RESUMEN

Leber congenital amaurosis (LCA)/early-onset severe retinal dystrophy (EOSRD) stand as primary causes of incurable childhood blindness. This study investigates the clinical and molecular architecture of syndromic and non-syndromic LCA/EOSRD within a Chilean cohort (67 patients/60 families). Leveraging panel sequencing, 95.5% detection was achieved, revealing 17 genes and 126 variants (32 unique). CRB1, LCA5, and RDH12 dominated (71.9%), with CRB1 being the most prevalent (43.8%). Notably, four unique variants (LCA5 p.Glu415*, CRB1 p.Ser1049Aspfs*40 and p.Cys948Tyr, RDH12 p.Leu99Ile) constituted 62.7% of all disease alleles, indicating their importance for targeted analysis in Chilean patients. This study underscores a high degree of inbreeding in Chilean families affected by pediatric retinal blindness, resulting in a limited mutation repertoire. Furthermore, it complements and reinforces earlier reports, indicating the involvement of ADAM9 and RP1 as uncommon causes of LCA/EOSRD. These data hold significant value for patient and family counseling, pharmaceutical industry endeavors in personalized medicine, and future enrolment in gene therapy-based treatments, particularly with ongoing trials (LCA5) or advancing preclinical developments (CRB1 and RDH12).


Asunto(s)
Mutación , Distrofias Retinianas , Humanos , Distrofias Retinianas/genética , Distrofias Retinianas/terapia , Distrofias Retinianas/diagnóstico , Chile/epidemiología , Masculino , Femenino , Niño , Preescolar , Oxidorreductasas de Alcohol/genética , Proteínas de la Membrana/genética , Proteínas del Ojo/genética , Amaurosis Congénita de Leber/genética , Amaurosis Congénita de Leber/terapia , Amaurosis Congénita de Leber/diagnóstico , Linaje , Proteínas del Tejido Nervioso/genética , Adolescente , Alelos , Variación Genética , Enfermedades Hereditarias del Ojo
2.
Am J Hum Genet ; 106(6): 859-871, 2020 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-32470375

RESUMEN

Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD.


Asunto(s)
Enfermedades Hereditarias del Ojo/genética , Proteínas de Unión al GTP/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Mutación con Pérdida de Función , Miopía/genética , Proteínas del Tejido Nervioso/genética , Ceguera Nocturna/genética , Adulto , Alelos , Empalme Alternativo , Encéfalo/metabolismo , Línea Celular , Niño , Preescolar , Diagnóstico Diferencial , Salud de la Familia , Femenino , Francia , Proteínas de Unión al GTP/química , Proteínas de Unión al GTP/metabolismo , Glucosa/metabolismo , Humanos , Secreción de Insulina , Masculino , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/metabolismo , Páncreas/metabolismo , Linaje , Retina/metabolismo , Arabia Saudita , Senegal
3.
Hum Mol Genet ; 27(15): 2689-2702, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29771326

RESUMEN

CEP290 mutations cause a spectrum of ciliopathies from Leber congenital amaurosis type 10 (LCA10) to embryo-lethal Meckel syndrome (MKS). Using panel-based molecular diagnosis testing for inherited retinal diseases, we identified two individuals with some preserved vision despite biallelism for presumably truncating CEP290 mutations. The first one carried a homozygous 1 base pair deletion in Exon 17, introducing a premature termination codon (PTC) in Exon 18 (c.1666del; p.Ile556Phefs*17). mRNA analysis revealed a basal exon skipping (BES) of Exon 18, providing mutant cells with the ability to escape protein truncation, while disrupting the reading frame in controls. The second individual harbored compound heterozygous nonsense mutations in Exon 8 (c.508A>T, p.Lys170*) and Exon 32 (c.4090G>T, p.Glu1364*), respectively. Some CEP290 lacking Exon 8 were detected in mutant fibroblasts but not in controls whereas some skipping of Exon 32 occurred in both lines, but with higher amplitude in the mutant. Considering that the deletion of either exon maintains the reading frame in either line, skipping in mutant cells likely involves nonsense-associated altered splicing alone (Exon 8), or with BES (Exon 32). Skipping of PTC-containing exons in mutant cells allowed production of CEP290 isoforms with preserved ability to assemble into a high molecular weight complex and to interact efficiently with proteins important for cilia formation and intraflagellar trafficking. In contrast, studying LCA10 and MKS fibroblasts we show moderate to severe cilia alterations, providing support for a correlation between disease severity and the ability of cells to express shortened, yet functional, CEP290 isoforms.


Asunto(s)
Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Enfermedades de la Retina/genética , Adolescente , Adulto , Autoantígenos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Centrosoma/metabolismo , Niño , Cilios/fisiología , Codón sin Sentido , Codón de Terminación , Proteínas del Citoesqueleto , Exones , Proteínas del Ojo/metabolismo , Femenino , Fibroblastos/fisiología , Humanos , Masculino , Mutación , Transporte de Proteínas , Empalme del ARN , Enfermedades de la Retina/etiología , Enfermedades de la Retina/patología , Proteínas Supresoras de Tumor/metabolismo
4.
Am J Hum Genet ; 101(6): 1006-1012, 2017 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-29198720

RESUMEN

Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypical association of LCA with early-onset hearing loss, we identified two heterozygous mutations affecting Arg391 in ß-tubulin 4B isotype-encoding (TUBB4B). Inspection of the atomic structure of the microtubule (MT) protofilament reveals that the ß-tubulin Arg391 residue contributes to a binding pocket that interacts with α-tubulin contained in the longitudinally adjacent αß-heterodimer, consistent with a role in maintaining MT stability. Functional analysis in cultured cells overexpressing FLAG-tagged wild-type or mutant TUBB4B as well as in primary skin-derived fibroblasts showed that the mutant TUBB4B is able to fold, form αß-heterodimers, and co-assemble into the endogenous MT lattice. However, the dynamics of growing MTs were consistently altered, showing that the mutations have a significant dampening impact on normal MT growth. Our findings provide a link between sensorineural disease and anomalies in MT behavior and describe a syndromic LCA unrelated to ciliary dysfunction.


Asunto(s)
Amaurosis Congénita de Leber/genética , Microtúbulos/genética , Tubulina (Proteína)/genética , Adulto , Sitios de Unión/genética , Células Cultivadas , Niño , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Microtúbulos/metabolismo , Persona de Mediana Edad , Mutación Missense/genética , Células Fotorreceptoras/metabolismo , Tubulina (Proteína)/metabolismo , Secuenciación del Exoma
5.
Adv Exp Med Biol ; 1185: 233-238, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31884617

RESUMEN

The specific association of Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (LCA-like) with sensorineural hearing loss (SHL) is uncommon. Recently, we ascribed some of these distinctive associations to dominant and de novo mutations in the ß-tubulin 4B isotype-encoding gene (TUBB4B), providing a link between a sensorineural disease and anomalies in microtubules behavior. Here, we report 12 sporadic cases with LCA/SHL or LCA-like/SHL and no TUBB4B mutation. Trio-based whole exome sequencing (WES) identified disease-causing mutations in 5/12 cases. Four out of five carried biallelic mutations in PEX1 (1/4) or PEX6 (3/4), involved in peroxisome biogenesis disorders from Zellweger syndrome characterized by severe neurologic and neurosensory dysfunctions, craniofacial abnormalities, and liver dysfunction to Heimler syndrome associating SHL, enamel hypoplasia of the secondary dentition, nail abnormalities, and occasional retinal disease. Upon reexamination, the index case carrying PEX1 mutations, a 4-year-old girl, presented additional symptoms consistent with Zellweger syndrome. Reexamination of individuals with PEX6 mutations (1/3 unavailable) revealed normal nails but enamel hypoplasia affecting one primary teeth in a 4-year-old girl and severe enamel hypoplasia of primary teeth hidden by dental prosthesis in a 50-year-old male, describing a novel PEX6-associated disease of the Zellweger/Heimler spectrum. Finally, hemizygosity for a CACNA1F mutation was identified in an 18-year-old male addressed for LCA/SHL, redirecting the retinal diagnosis to congenital stationary night blindness (CSNB2A). Consistent with the pure CSNB2A retinal involvement, SHL was ascribed to biallelic mutations in another gene, STRC, involved in nonprogressive DFNB16 deafness.


Asunto(s)
Pérdida Auditiva Sensorineural/genética , Amaurosis Congénita de Leber/genética , Distrofias Retinianas/genética , ATPasas Asociadas con Actividades Celulares Diversas/genética , Adolescente , Canales de Calcio Tipo L/genética , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Uñas Malformadas , Linaje
6.
Adv Exp Med Biol ; 1185: 189-195, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31884610

RESUMEN

CEP290 mutations cause a spectrum of ciliopathies, including Leber congenital amaurosis. Milder retinal diseases have been ascribed to exclusion of CEP290 mutant exons through basal exon skipping (BES) and/or nonsense-associated altered splicing (NAS). Here, we report two siblings with some preserved vision despite biallelism for presumably severe CEP290 mutations: a maternal splice site change in intron 18 (c.1824 + 3A > G) and a paternal c.6869dup (p.Asn2290Lysfs∗6) in exon 50 that introduces a premature termination codon (PTC) within the same exon. Analyzing mRNAs from fibroblasts of the two siblings, we detected no BES or NAS which could have enabled the production of PTC-free CEP290 isoforms from the paternal allele. In contrast, we reveal partial alteration of exon 18 donor splice site, allowing the transcription of some correctly spliced CEP290 mRNAs from the maternal allele which likely account for the mild retinal disease. This observation adds further variability to the mechanisms underlying CEP290 pleiotropy.


Asunto(s)
Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Codón sin Sentido , Proteínas del Citoesqueleto/genética , Exones , Empalme del ARN , Enfermedades de la Retina/genética , Humanos , Mutación , Hermanos
7.
Hum Mutat ; 39(7): 983-992, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29688594

RESUMEN

Ciliopathies represent a wide spectrum of rare diseases with overlapping phenotypes and a high genetic heterogeneity. Among those, IFT140 is implicated in a variety of phenotypes ranging from isolated retinis pigmentosa to more syndromic cases. Using whole-genome sequencing in patients with uncharacterized ciliopathies, we identified a novel recurrent tandem duplication of exon 27-30 (6.7 kb) in IFT140, c.3454-488_4182+2588dup p.(Tyr1152_Thr1394dup), missed by whole-exome sequencing. Pathogenicity of the mutation was assessed on the patients' skin fibroblasts. Several hundreds of patients with a ciliopathy phenotype were screened and biallelic mutations were identified in 11 families representing 12 pathogenic variants of which seven are novel. Among those unrelated families especially with a Mainzer-Saldino syndrome, eight carried the same tandem duplication (two at the homozygous state and six at the heterozygous state). In conclusion, we demonstrated the implication of structural variations in IFT140-related diseases expanding its mutation spectrum. We also provide evidences for a unique genomic event mediated by an Alu-Alu recombination occurring on a shared haplotype. We confirm that whole-genome sequencing can be instrumental in the ability to detect structural variants for genomic disorders.


Asunto(s)
Proteínas Portadoras/genética , Ataxia Cerebelosa/genética , Ciliopatías/genética , Retinitis Pigmentosa/genética , Secuenciación Completa del Genoma , Elementos Alu/genética , Ataxia Cerebelosa/patología , Ciliopatías/patología , Bases de Datos Genéticas , Exones/genética , Femenino , Heterocigoto , Homocigoto , Humanos , Masculino , Mutación/genética , Linaje , Fenotipo , Retinitis Pigmentosa/patología
9.
Am J Hum Genet ; 94(6): 891-7, 2014 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-24814191

RESUMEN

Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs(∗)48] and c.3709C>T [p.Arg1237(∗)]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983C>G [p.Ser328(∗)] and c.6232G>T [p.Glu2078(∗)]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes.


Asunto(s)
Ceguera Cortical/genética , Epilepsia/genética , Proteínas Activadoras de GTPasa/genética , Discapacidad Intelectual/genética , Niño , Preescolar , Epilepsias Mioclónicas/genética , Exoma , Femenino , Proteínas Activadoras de GTPasa/metabolismo , Genes Recesivos , Factores de Intercambio de Guanina Nucleótido/genética , Heterocigoto , Homocigoto , Humanos , Lactante , Masculino , Mutación , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Espasmos Infantiles/genética
10.
J Med Genet ; 52(10): 657-65, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26275418

RESUMEN

BACKGROUND: Bidirectional intraflagellar transport (IFT) consists of two major protein complexes, IFT-A and IFT-B. In contrast to the IFT-B complex, all components of IFT-A have recently been linked to human ciliopathies when defective. We therefore hypothesised that mutations in additional IFT-B encoding genes can be found in patients with multisystemic ciliopathies. METHODS: We screened 1628 individuals with reno-ocular ciliopathies by targeted next-generation sequencing of ciliary candidate genes, including all IFT-B encoding genes. RESULTS: Consequently, we identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. Further, we detected a loss-of-stop mutation with extension of the deduced protein by 10 amino acids in an individual with neuronal ceroid lipofuscinosis-1. This proband presented with retinal dystrophy and brain lesions including cerebellar atrophy, a phenotype to which the IFT81 variant might contribute. Cultured fibroblasts of this latter affected individual showed a significant decrease in ciliated cell abundance compared with controls and increased expression of the transcription factor GLI2 suggesting deranged sonic hedgehog signalling. CONCLUSIONS: This work describes identification of mutations of IFT81 in individuals with symptoms consistent with the clinical spectrum of ciliopathies. It might represent the rare case of a core IFT-B complex protein found associated with human disease. Our data further suggest that defects in the IFT-B core are an exceedingly rare finding, probably due to its indispensable role for ciliary assembly in development.


Asunto(s)
Cilios/genética , Cilios/patología , Ojo/patología , Riñón/patología , Proteínas Musculares/genética , Humanos , Mutación , Análisis de Secuencia de ADN
11.
Am J Hum Genet ; 90(5): 864-70, 2012 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-22503633

RESUMEN

Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy. Through a combination of ciliome resequencing and Sanger sequencing, we identified IFT140 mutations in six MSS families and in a family with the clinically overlapping Jeune syndrome. IFT140 is one of the six currently known components of the intraflagellar transport complex A (IFT-A) that regulates retrograde protein transport in ciliated cells. Ciliary abundance and localization of anterograde IFTs were altered in fibroblasts of affected individuals, a result that supports the pivotal role of IFT140 in proper development and function of ciliated cells.


Asunto(s)
Proteínas Portadoras/genética , Ataxia Cerebelosa/genética , Mutación , Retinitis Pigmentosa/genética , Adolescente , Alelos , Proteínas Portadoras/metabolismo , Niño , Preescolar , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Masculino , Linaje , Transporte de Proteínas/genética
12.
Hum Mutat ; 35(1): 137-46, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24166846

RESUMEN

Joubert syndrome (JS) is characterized by a distinctive cerebellar structural defect, namely the << molar tooth sign >>. JS is genetically heterogeneous, involving 20 genes identified to date, which are all required for cilia biogenesis and/or function. In a consanguineous family with JS associated with optic nerve coloboma, kidney hypoplasia, and polydactyly, combined exome sequencing and mapping identified a homozygous splice-site mutation in PDE6D, encoding a prenyl-binding protein. We found that pde6d depletion in zebrafish leads to renal and retinal developmental anomalies and wild-type but not mutant PDE6D is able to rescue this phenotype. Proteomic analysis identified INPP5E, whose mutations also lead to JS or mental retardation, obesity, congenital retinal dystrophy, and micropenis syndromes, as novel prenyl-dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. Furthermore, mutant PDE6D is unable to bind to GTP-bound ARL3, which acts as a cargo-release factor for PDE6D-bound INPP5E. Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. This study identifies PDE6D as a novel JS disease gene and provides the first evidence of prenyl-binding-dependent trafficking in ciliopathies.


Asunto(s)
Enfermedades Cerebelosas/genética , Enfermedades Cerebelosas/metabolismo , Cilios/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/metabolismo , Anomalías del Ojo/genética , Anomalías del Ojo/metabolismo , Enfermedades Renales Quísticas/genética , Enfermedades Renales Quísticas/metabolismo , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/metabolismo , Retina/anomalías , Factores de Ribosilacion-ADP/metabolismo , Anomalías Múltiples , Animales , Cerebelo/anomalías , Exoma , Femenino , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , Masculino , Modelos Moleculares , Linaje , Prenilación de Proteína , Proteómica , Retina/metabolismo , Análisis de Secuencia de ADN , Pez Cebra/anomalías , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo
13.
Biochim Biophys Acta ; 1830(6): 3719-33, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23500070

RESUMEN

BACKGROUND: Hereditary optic neuropathies (HONs) are a heterogeneous group of disorders that affect retinal ganglion cells (RGCs) and axons that form the optic nerve. Leber's Hereditary Optic Neuropathy and the autosomal dominant optic atrophy related to OPA1 mutations are the most common forms. Nonsyndromic autosomal recessive optic neuropathies are rare and their existence has been long debated. We recently identified the first gene responsible for these conditions, TMEM126A. This gene is highly expressed in retinal cellular compartments enriched in mitochondria and supposed to encode a mitochondrial transmembrane protein of unknown function. METHODS: A specific polyclonal antibody targeting the TMEM126A protein has been generated. Quantitative fluorescent in situ hybridization, cellular fractionation, mitochondrial membrane association study, mitochondrial sub compartmentalization analysis by both proteolysis assays and transmission electron microscopy, and expression analysis of truncated TMEM126A constructs by immunofluorescence confocal microscopy were carried out. RESULTS: TMEM126A mRNAs are strongly enriched in the vicinity of mitochondria and encode an inner mitochondrial membrane associated cristae protein. Moreover, the second transmembrane domain of TMEM126A is required for its mitochondrial localization. CONCLUSIONS: TMEM126A is a mitochondrial located mRNA (MLR) that may be translated in the mitochondrial surface and the protein is subsequently imported to the inner membrane. These data constitute the first step toward a better understanding of the mechanism of action of TMEM126A in RGCs and support the importance of mitochondrial dysfunction in the pathogenesis of HON. GENERAL SIGNIFICANCE: Local translation of nuclearly encoded mitochondrial mRNAs might be a mechanism for rapid onsite supply of mitochondrial membrane proteins.


Asunto(s)
Proteínas de la Membrana/biosíntesis , Membranas Mitocondriales/metabolismo , Proteínas Mitocondriales/biosíntesis , Biosíntesis de Proteínas , Células Ganglionares de la Retina/metabolismo , Animales , Células COS , Chlorocebus aethiops , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/metabolismo , Enfermedades Genéticas Congénitas/patología , Humanos , Proteínas de la Membrana/genética , Membranas Mitocondriales/patología , Proteínas Mitocondriales/genética , Mutación , Enfermedades del Nervio Óptico/genética , Enfermedades del Nervio Óptico/metabolismo , Enfermedades del Nervio Óptico/patología , Estructura Terciaria de Proteína , ARN Mensajero/genética , ARN Mensajero/metabolismo , Células Ganglionares de la Retina/patología
14.
Am J Hum Genet ; 84(4): 493-8, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19327736

RESUMEN

Nonsyndromic autosomal-recessive optic neuropathies are rare conditions of unknown genetic and molecular origin. Using an approach of whole-genome homozygosity mapping and positional cloning, we have identified the first gene, to our knowledge, responsible for this condition, TMEM126A, in a large multiplex inbred Algerian family and subsequently in three other families originating from the Maghreb. TMEM126A is conserved in higher eukaryotes and encodes a transmembrane mitochondrial protein of unknown function, supporting the view that mitochondrial dysfunction may be a hallmark of inherited optic neuropathies including isolated autosomal-recessive forms.


Asunto(s)
Proteínas Mitocondriales/genética , Mutación , Atrofias Ópticas Hereditarias/genética , Argelia , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Células COS , Chlorocebus aethiops , Codón sin Sentido , Femenino , Expresión Génica , Genes Recesivos , Haplotipos , Humanos , Masculino , Ratones , Proteínas Mitocondriales/química , Proteínas Mitocondriales/metabolismo , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Retina/metabolismo , Homología de Secuencia de Aminoácido , Transfección
15.
JAMA Ophthalmol ; 140(12): 1163-1173, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36264558

RESUMEN

Importance: Congenital stationary night blindness (CSNB) is an inherited stationary retinal disorder that is clinically and genetically heterogeneous. To date, the genetic association between some cases with CSNB and an unusual complex clinical picture is unclear. Objective: To describe an unreported CSNB phenotype and the associated gene defect in 3 patients from 2 unrelated families. Design, Setting, and Participants: This retrospective case series was conducted in 2021 and 2022 at a national referral center for rare ocular diseases. Data for 3 patients from a cohort of 140 genetically unsolved CSNB cases were analyzed clinically and genetically. Exposures: Complete ocular examination including full-field electroretinography and multimodal fundus imaging (spectral-domain optical coherence tomography, color, infrared reflectance, and short-wavelength autofluorescence photographs) were performed. The gene defect was identified by exome sequencing and confirmed by Sanger sequencing and co-segregation analysis in 1 family. Screening was performed for genetically unsolved CSNB cases for VSX2 variants by direct Sanger sequencing. Main Outcomes and Measures: Ocular and molecular biology findings. Results: The series included 3 patients whose clinical investigations occurred at ages in the early 30s, younger than 12 years, and in the mid 40s. They had nystagmus, low stable visual acuity, and myopia from birth and experienced night blindness. Two older patients had bilateral lens luxation and underwent lens extraction. Full-field electroretinography revealed an electronegative Schubert-Bornschein appearance, combining characteristics of incomplete and complete CSNB, affecting the function of rod and cone ON- and OFF-bipolar cells. Exome sequencing and co-segregation analysis in a consanguineous family with 2 affected members identified a homozygous variant in VSX2. Subsequently, screening of the CSNB cohort identified another unrelated patient harboring a distinct VSX2 variant. Conclusions and Relevance: This case series revealed a peculiar pan-bipolar cell retinopathy with lens luxation associated with variants in VSX2. Clinicians should be aware of this association and VSX2 added to CSNB diagnostic gene panels.


Asunto(s)
Enfermedades Hereditarias del Ojo , Enfermedades Genéticas Ligadas al Cromosoma X , Miopía , Ceguera Nocturna , Humanos , Ceguera Nocturna/diagnóstico , Ceguera Nocturna/genética , Estudios Retrospectivos , Mutación , Enfermedades Hereditarias del Ojo/diagnóstico , Enfermedades Hereditarias del Ojo/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Miopía/diagnóstico , Miopía/genética , Electrorretinografía , Linaje , Factores de Transcripción/genética , Proteínas de Homeodominio/genética
16.
Genes (Basel) ; 12(2)2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670832

RESUMEN

Leber congenital amaurosis (LCA) encompasses the earliest and most severe retinal dystrophies and can occur as a non-syndromic or a syndromic disease. Molecular diagnosis in LCA is of particular importance in clinical decision-making and patient care since it can provide ocular and extraocular prognostics and identify patients eligible to develop gene-specific therapies. Routine high-throughput molecular testing in LCA yields 70%-80% of genetic diagnosis. In this study, we aimed to investigate the non-coding regions of one non-syndromic LCA gene, RPGRIP1, in a series of six families displaying one single disease allele after a gene-panel screening of 722 LCA families which identified 26 biallelic RPGRIP1 families. Using trio-based high-throughput whole locus sequencing (WLS) for second disease alleles, we identified a founder deep intronic mutation (NM_020366.3:c.1468-128T>G) in 3/6 families. We employed Sanger sequencing to search for the pathologic variant in unresolved LCA cases (106/722) and identified three additional families (two homozygous and one compound heterozygous with the NM_020366.3:c.930+77A>G deep intronic change). This makes the c.1468-128T>G the most frequent RPGRIP1 disease allele (8/60, 13%) in our cohort. Studying patient lymphoblasts, we show that the pathologic variant creates a donor splice-site and leads to the insertion of the pseudo-exon in the mRNA, which we were able to hamper using splice-switching antisense oligonucleotides (AONs), paving the way to therapies.


Asunto(s)
Proteínas del Citoesqueleto/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Amaurosis Congénita de Leber/genética , Distrofias Retinianas/genética , Adolescente , Adulto , Alelos , Niño , Preescolar , Análisis Mutacional de ADN , Exones , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Intrones/genética , Amaurosis Congénita de Leber/patología , Masculino , Mutación/genética , Patología Molecular , Linaje , Distrofias Retinianas/patología , Adulto Joven
17.
Hum Mutat ; 31(3): E1241-50, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20104588

RESUMEN

Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration. It may present as a congenital stationary cone-rod dystrophy (LCA type I) or a progressive yet severe rod-cone dystrophy (LCA type II). Twelve LCA genes have been identified, three of which account for Type I and nine for LCA type II. All proteins encoded by these genes but two are preferentially expressed in the retina and are responsible for non-syndromic LCA only. By contrast LCA5 and CEP290 are widely expressed and mutations in this latter result in a variety of phenotypes from non-syndromic retinal degeneration to pleiotropic disorders including senior-Loken (SNLS) and Joubert syndromes (JBTS). Recently, mutations in the widely expressed gene SPATA7 were reported to cause LCA or juvenile retinitis pigmentosa. The purpose of this study was i) to determine the level of expression of two major alternative SPATA7 transcripts in a large range of tissues and ii) to assess the involvement of this novel gene in a large cohort of unrelated patients affected with LCA (n = 134). Here, we report high SPATA7expression levels in retina, brain and testis with differential expression of the two transcripts. SPATA7 mutations were identified in few families segregating non-syndromic LCA (n = 4/134). Six different mutations were identified, four of which are novel; All affected both SPATA7 transcripts. The clinical evaluation of patients suggested that SPATA7 mutations account for the rod-cone dystrophy type of the disease.


Asunto(s)
Proteínas de Unión al ADN/genética , Amaurosis Congénita de Leber/genética , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Mutación , Fenotipo , Retina/patología , Retinitis Pigmentosa/genética , Síndrome
18.
Am J Med Genet A ; 149A(10): 2173-80, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19764032

RESUMEN

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.


Asunto(s)
Anomalías Múltiples/genética , Antígenos de Neoplasias/genética , Cilios , Proteínas de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Secuencia de Bases , Proteínas de Ciclo Celular , Cilios/genética , Cilios/patología , Proteínas del Citoesqueleto , Análisis Mutacional de ADN , Femenino , Feto/metabolismo , Feto/patología , Eliminación de Gen , Pruebas Genéticas , Humanos , Proteínas de Neoplasias/metabolismo , ARN Mensajero/análisis , Síndrome
19.
Genes (Basel) ; 10(5)2019 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-31091803

RESUMEN

Mutations in CEP290 encoding a centrosomal protein important to cilia formation cause a spectrum of diseases, from isolated retinal dystrophies to multivisceral and sometimes embryo-lethal ciliopathies. In recent years, endogenous and/or selective non-canonical exon skipping of mutant exons have been documented in attenuated retinal disease cases. This observation led us to consider targeted exon skipping to bypass protein truncation resulting from a recurrent mutation in exon 36 (c.4723A > T, p.Lys1575*) causing isolated retinal ciliopathy. Here, we report two unrelated individuals (P1 and P2), carrying the mutation in homozygosity but affected with early-onset severe retinal dystrophy and congenital blindness, respectively. Studying skin-derived fibroblasts, we observed basal skipping and nonsense associated-altered splicing of exon 36, producing low (P1) and very low (P2) levels of CEP290 products. Consistent with a more severe disease, fibroblasts from P2 exhibited reduced ciliation compared to P1 cells displaying normally abundant cilia; both lines presented however significantly elongated cilia, suggesting altered axonemal trafficking. Antisense oligonucleotides (AONs)-mediated skipping of exon 36 increased the abundance of the premature termination codon (PTC)-free mRNA and protein, reduced axonemal length and improved cilia formation in P2 but not in P1 expressing higher levels of skipped mRNA, questioning AON-mediated exon skipping to treat patients carrying the recurrent c.4723A > T mutation.


Asunto(s)
Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Distrofias Retinianas/genética , Codón sin Sentido , Exones/genética , Anomalías del Ojo/genética , Enfermedades Hereditarias del Ojo/genética , Humanos , Masculino , Proteínas de Neoplasias/genética , Oligonucleótidos Antisentido/genética , Empalme del ARN , Retina/metabolismo , Distrofias Retinianas/fisiopatología
20.
Eur J Hum Genet ; 16(1): 115-23, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17684531

RESUMEN

The mosaic pattern of haplotypes observed around a single mutation results from one or several founder events. The difficulties involved in calculating the age of the variant are greatly reduced by assuming a single event, but this simplification may bias analysis of the genealogy of the mutation. However, if it is assumed that more than one founder event occurred, the number of genealogies is very large and the likelihood of every possible tree could not be realistically calculated. A multipoint approach is required, given the number of independent variables needed to describe a complex bifurcating genealogy. Starting from the observation that a limited number of parameters is needed for calculation of the simplest models of bifurcating genealogies, we show that the probability density of a two-ancestor model genealogy can be simply described as an algebraic function in a closed form, two coalescence times being calculated simultaneously without compromising accuracy. Implementation in a Bayesian framework is facilitated by the simplicity of the function, which describes the reciprocal relationship between the region of complete linkage disequilibrium and the branch length of the tree. We illustrate the use of haplotype information about allele-sharing decay around a mutation as a genetic clock, using data for two GUCY2D mutations in Mediterranean populations.


Asunto(s)
Genética de Población , Guanilato Ciclasa/genética , Modelos Genéticos , Mutación , Receptores de Superficie Celular/genética , África del Norte/etnología , Teorema de Bayes , Cartilla de ADN/genética , Femenino , Efecto Fundador , Francia , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Modelos Estadísticos , Atrofia Óptica Hereditaria de Leber/genética , Polimorfismo de Nucleótido Simple , Portugal/etnología , Eliminación de Secuencia , Factores de Tiempo
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