RESUMEN
Primary cilia are antenna-like organelles on the surface of most mammalian cells that receive sonic hedgehog (Shh) signaling in embryogenesis and carcinogenesis. Cellular cholesterol functions as a direct activator of a seven-transmembrane oncoprotein called Smoothened (Smo) and thereby induces Smo accumulation on the ciliary membrane where it transduces the Shh signal. However, how cholesterol is supplied to the ciliary membrane remains unclear. Here, we report that peroxisomes are essential for the transport of cholesterol into the ciliary membrane. Zellweger syndrome (ZS) is a peroxisome-deficient hereditary disorder with several ciliopathy-related features and cells from these patients showed a reduced cholesterol level in the ciliary membrane. Reverse genetics approaches revealed that the GTP exchange factor Rabin8, the Rab GTPase Rab10, and the microtubule minus-end-directed kinesin KIFC3 form a peroxisome-associated complex to control the movement of peroxisomes along microtubules, enabling communication between peroxisomes and ciliary pocket membranes. Our findings suggest that insufficient ciliary cholesterol levels may underlie ciliopathies.
Asunto(s)
Colesterol/metabolismo , Cilios/metabolismo , Síndrome de Zellweger/metabolismo , Células Cultivadas , Colesterol/genética , Cilios/genética , Cilios/patología , Quinasas del Centro Germinal/genética , Quinasas del Centro Germinal/metabolismo , Humanos , Cinesinas/genética , Cinesinas/metabolismo , Microtúbulos/genética , Microtúbulos/metabolismo , Microtúbulos/patología , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Síndrome de Zellweger/genética , Síndrome de Zellweger/patología , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismoRESUMEN
PURPOSE: Zellweger spectrum disorders (ZSDs) are known as autosomal recessive disorders caused by defective peroxisome biogenesis due to bi-allelic pathogenic variants in any of at least 13 different PEX genes. Here, we report 2 unrelated patients who present with an autosomal dominant ZSD. METHODS: We performed biochemical and genetic studies in blood and skin fibroblasts of the patients and demonstrated the pathogenicity of the identified PEX14 variants by functional cell studies. RESULTS: We identified 2 different single heterozygous de novo variants in the PEX14 genes of 2 patients diagnosed with ZSD. Both variants cause messenger RNA mis-splicing, leading to stable expression of similar C-terminally truncated PEX14 proteins. Functional studies indicated that the truncated PEX14 proteins lost their function in peroxisomal matrix protein import and cause increased degradation of peroxisomes, ie, pexophagy, thus exerting a dominant-negative effect on peroxisome functioning. Inhibition of pexophagy by different autophagy inhibitors or genetic knockdown of the peroxisomal autophagy receptor NBR1 resulted in restoration of peroxisomal functions in the patients' fibroblasts. CONCLUSION: Our finding of an autosomal dominant ZSD expands the genetic repertoire of ZSDs. Our study underscores that single heterozygous variants should not be ignored as possible genetic cause of diseases with an established autosomal recessive mode of inheritance.
Asunto(s)
Síndrome de Zellweger , Humanos , Alelos , Peroxisomas/genética , Peroxisomas/metabolismo , Transporte de Proteínas/fisiología , Proteínas/genética , Síndrome de Zellweger/genéticaRESUMEN
Zellweger spectrum disorder (ZSD) is a group of autosomal recessive disorders caused by biallelic pathogenic variants in any one of the 13 PEX genes essential for peroxisomal biogenesis. We report a cohort of nine infants who presented at birth with severe neonatal features suggestive of ZSD and found to be homozygous for a variant in PEX6 (NM_000287.4:c.1409G > C[p.Gly470Ala]). All were of Mixtec ancestry and identified by the California Newborn Screening (NBS) Program to have elevated C26:0-lysophosphatidylcholine but no reportable variants in ABCD1. The clinical and biochemical features of this cohort are described within. Gly470Ala may represent a founder variant in the Mixtec population of Central California. ZSD should be considered in patients who present at birth with severe hypotonia and enlarged fontanelles, especially in the setting of an abnormal NBS, Mixtec ancestry, or family history of infant death. There is a need to further characterize the natural history of ZSD, the Gly470Ala variant, and expand upon possible genotype-phenotype correlations.
Asunto(s)
Síndrome de Zellweger , Humanos , Recién Nacido , Síndrome de Zellweger/diagnóstico , Síndrome de Zellweger/genética , Síndrome de Zellweger/patología , ATPasas Asociadas con Actividades Celulares Diversas/genética , Estudios de Asociación Genética , Tamizaje Neonatal , LisofosfatidilcolinasRESUMEN
Peroxisomal biogenesis disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs-Zellweger spectrum disorder (ZSD)-is caused by mutations in peroxin genes that result in both non-functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter-organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs.
Asunto(s)
Trastorno Peroxisomal , Síndrome de Zellweger , Humanos , Mitocondrias/genética , Peroxinas/metabolismo , Trastorno Peroxisomal/genética , Trastorno Peroxisomal/metabolismo , Peroxisomas/metabolismo , Síndrome de Zellweger/genética , Síndrome de Zellweger/metabolismoRESUMEN
Zellweger spectrum disorders (ZSD) are rare autosomal recessive disorders caused by defects in peroxisome biogenesis factor (PEX; peroxin) genes leading to impaired transport of peroxisomal proteins with peroxisomal targeting signals (PTS). Four patients, including a pair of homozygotic twins, diagnosed as ZSD by genetic study with different clinical presentations and outcomes as well as various novel mutations are described here. A total of 3 novel mutations, including a nonsense, a frameshift, and a splicing mutation, in PEX1 from ZSD patients were identified and unequivocally confirmed that the p.Ile989Thr mutant PEX1 exhibited temperature-sensitive characteristics and is associated with milder ZSD. The nature of the p.Ile989Thr mutant exhibited different characteristics from that of the other previously identified temperature-sensitive p.Gly843Asp PEX1 mutant. Transcriptome profiles under nonpermissive vs. permissive conditions were explored to facilitate the understanding of p.Ile989Thr mutant PEX1. Further investigation of molecular mechanisms may help to clarify potential genetic causes that could modify the clinical presentation of ZSD.
Asunto(s)
Síndrome de Zellweger , Humanos , Niño , Síndrome de Zellweger/genética , Síndrome de Zellweger/complicaciones , Síndrome de Zellweger/metabolismo , Temperatura , ATPasas Asociadas con Actividades Celulares Diversas/genética , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Fibroblastos/metabolismo , Mutación/genéticaRESUMEN
Peroxisomes function together with mitochondria in a number of essential biochemical pathways, from bile acid synthesis to fatty acid oxidation. Peroxisomes grow and divide from pre-existing organelles, but can also emerge de novo in the cell. The physiological regulation of de novo peroxisome biogenesis remains unclear, and it is thought that peroxisomes emerge from the endoplasmic reticulum in both mammalian and yeast cells. However, in contrast to the yeast system, a number of integral peroxisomal membrane proteins are imported into mitochondria in mammalian cells in the absence of peroxisomes, including Pex3, Pex12, Pex13, Pex14, Pex26, PMP34 and ALDP. Overall, the mitochondrial localization of peroxisomal membrane proteins in mammalian cells has largely been considered a mis-targeting artefact in which de novo biogenesis occurs exclusively from endoplasmic reticulum-targeted peroxins. Here, in following the generation of new peroxisomes within human patient fibroblasts lacking peroxisomes, we show that the essential import receptors Pex3 and Pex14 target mitochondria, where they are selectively released into vesicular pre-peroxisomal structures. Maturation of pre-peroxisomes containing Pex3 and Pex14 requires fusion with endoplasmic reticulum-derived vesicles carrying Pex16, thereby providing full import competence. These findings demonstrate the hybrid nature of newly born peroxisomes, expanding their functional links to mitochondria.
Asunto(s)
Retículo Endoplásmico/metabolismo , Mitocondrias/metabolismo , Biogénesis de Organelos , Peroxisomas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Línea Celular , Fibroblastos/citología , Humanos , Membranas Intracelulares/metabolismo , Lipoproteínas/deficiencia , Lipoproteínas/genética , Lipoproteínas/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Peroxinas , Transporte de Proteínas , Proteínas Represoras/metabolismo , Síndrome de Zellweger/genética , Síndrome de Zellweger/patologíaRESUMEN
Peroxisome biogenesis disorders-Zellweger spectrum disorders (PBD-ZSD)-are primarily autosomal recessive disorders caused by mutations in any of 13 PEX genes involved in peroxisome assembly. Compared to other PEX-related disorders, some PEX16 defects are associated with an atypical phenotype consisting of spasticity, cerebellar dysfunction, preserved cognition, and prolonged survival. In this case series, medical records and brain MRIs from 7 patients with this PEX16 presentation were reviewed to further characterize this phenotype. Classic PBD features such as sensory deficits and amelogenesis imperfecta were absent in all 7 patients, while all patients had hypertonia. Five patients were noted to have dystonia and received a treatment trial of levodopa/carbidopa. Four treated patients had partial but significant improvements in their dystonia and tremors, and 1 patient had only minimal response. Brain MRI studies commonly showed T2/FLAIR hyperintensities in the brainstem, superior and middle cerebellar peduncles, corticospinal tracts, and splenium of the corpus callosum. Genetic analysis revealed novel biallelic variants in 3 probands (c.683C > T/372delG; c.692A > G homozygous; c.865C > G/451C > T) and 1 novel variant (c.956_958delCGC) in another proband. We demonstrated residual PEX16 protein amounts by immunoblotting in fibroblasts available from 5 patients with this atypical PEX16 disease (3 from this series, 2 previously reported), in contrast to the absence of PEX16 protein in fibroblasts from a patient with the severe ZSD presentation. This study further characterizes the phenotype of PEX16 defects by highlighting novel and distinctive clinical, neuroradiological, and molecular features of the disease and proposes a potential treatment for the dystonia. ClinicalTrials.gov Identifier: NCT01668186. Date of registration: January 2012.
Asunto(s)
Distonía , Síndrome de Zellweger , Femenino , Humanos , Masculino , Proteínas de la Membrana/genética , Mutación , Trastorno Peroxisomal , Síndrome de Zellweger/genética , Síndrome de Zellweger/metabolismoRESUMEN
Impaired peroxisome assembly caused by mutations in PEX genes results in a human congenital metabolic disease called Zellweger spectrum disorder (ZSD), which impacts the development and physiological function of multiple organs. In this study, we revealed a long-standing problem of heterogeneous peroxisome distribution among cell population, so called "peroxisomal mosaicism", which appears in patients with mild form of ZSD. We mutated PEX3 gene in HEK293 cells and obtained a mutant clone with peroxisomal mosaicism. We found that peroxisomal mosaicism can be reproducibly arise from a single cell, even if the cell has many or no peroxisomes. Using time-lapse imaging and a long-term culture experiment, we revealed that peroxisome biogenesis oscillates over a span of days; this was also confirmed in the patient's fibroblasts. During the oscillation, the metabolic activity of peroxisomes was maintained in the cells with many peroxisomes while depleted in the cells without peroxisomes. Our results indicate that ZSD patients with peroxisomal mosaicism have a cell population whose number and metabolic activities of peroxisomes can be recovered. This finding opens the way to develop novel treatment strategy for ZSD patients with peroxisomal mosaicism, who currently have very limited treatment options.
Asunto(s)
Trastorno Peroxisomal , Síndrome de Zellweger , Humanos , Mosaicismo , Células HEK293 , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Peroxisomas/genética , Peroxisomas/metabolismo , Síndrome de Zellweger/genética , Síndrome de Zellweger/metabolismo , Mutación , Fibroblastos/metabolismo , Trastorno Peroxisomal/genética , Trastorno Peroxisomal/metabolismo , Peroxinas/genética , Lipoproteínas/genéticaRESUMEN
Peroxisomal biogenesis disorders (PBDs) are a heterogeneous group of genetic diseases. Multiple peroxisomal pathways are impaired, and very long chain fatty acids (VLCFA) are the first line biomarkers for the diagnosis. The clinical presentation of PBDs may range from severe, lethal multisystemic disorders to milder, late-onset disease. The vast majority of PBDs belong to Zellweger Spectrum Disordes (ZSDs) and represents a continuum of overlapping clinical symptoms, with Zellweger syndrome being the most severe and Heimler syndrome the less severe disease. Mild clinical conditions frequently present normal or slight biochemical alterations, making the diagnosis of these patients challenging. In the present study we used a combined WES and RNA-seq strategy to diagnose a patient presenting with retinal dystrophy as the main clinical symptom. Results showed the patient was compound heterozygous for mutations in PEX1. VLCFA were normal, but retrospective analysis of lysosphosphatidylcholines (LPC) containing C22:0-C26:0 species was altered. This simple test could avoid the diagnostic odyssey of patients with mild phenotype, such as the individual described here, who was diagnosed very late in adult life. We provide functional data in cell line models that may explain the mild phenotype of the patient by demonstrating the hypomorphic nature of a deep intronic variant altering PEX1 mRNA processing.
Asunto(s)
Sordera , Pérdida Auditiva Sensorineural , Síndrome de Zellweger , Humanos , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , RNA-Seq , Estudios Retrospectivos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Síndrome de Zellweger/diagnóstico , Síndrome de Zellweger/genética , Pérdida Auditiva Sensorineural/genética , Biomarcadores , ARN Mensajero , Ácidos GrasosRESUMEN
A 5-year-old female patient, presented with"night blindness and poor hearing for 1 year"whose first diagnosis was Usher syndrome due to retinitis pigmentosa accompanied by sensorineural deafness. Compound heterozygous variants (c.5G>A, p.W2*/c.3022C>T, p.P1008S) of PEX1, the causative gene for Zellweger spectrum disorder was confirmed by targeted exome sequencing analysis. Permanent tooth enamel dysplasia, nail leukoplakia, and biochemical abnormalities of peroxisome which is consistent with mild Zellweger spectrum disorder were found when she followed up.
Asunto(s)
Retinitis Pigmentosa , Síndromes de Usher , Síndrome de Zellweger , ATPasas Asociadas con Actividades Celulares Diversas/genética , Preescolar , Femenino , Pruebas Genéticas , Humanos , Proteínas de la Membrana/genética , Mutación , Linaje , Síndromes de Usher/genética , Síndrome de Zellweger/diagnóstico , Síndrome de Zellweger/genéticaRESUMEN
Peroxisomes play an essential role in cellular homeostasis by regulating lipid metabolism and the conversion of reactive oxygen species (ROS). Several peroxisomal proteins, known as peroxins (PEXs), control peroxisome biogenesis and degradation. Various mutations in the PEX genes are genetic causes for the development of inheritable peroxisomal-biogenesis disorders, such as Zellweger syndrome. Among the peroxins, PEX1 defects are the most common mutations in Zellweger syndrome. PEX1 is an AAA-ATPase that regulates the recycling of PEX5, which is essential for importing peroxisome matrix proteins. However, the post-transcriptional regulation of PEX1 is largely unknown. Here, we showed that heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) controls PEX1 expression. In addition, we found that depletion of HNRNPA1 induces autophagic degradation of peroxisome, which is blocked in ATG5-knockout cells. In addition, depletion of HNRNPA1 increased peroxisomal ROS levels. Inhibition of the generation of peroxisomal ROS by treatment with NAC significantly suppressed pexophagy in HNRNPA1-deficient cells. Taken together, our results suggest that depletion of HNRNPA1 increases peroxisomal ROS and pexophagy by downregulating PEX1 expression.
Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Ribonucleoproteína Nuclear Heterogénea A1/metabolismo , Macroautofagia/fisiología , Proteínas de la Membrana/metabolismo , Peroxisomas/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/genética , Proteína 5 Relacionada con la Autofagia/antagonistas & inhibidores , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Células Cultivadas , Regulación hacia Abajo , Técnicas de Inactivación de Genes , Células HCT116 , Células HeLa , Ribonucleoproteína Nuclear Heterogénea A1/deficiencia , Ribonucleoproteína Nuclear Heterogénea A1/genética , Humanos , Macroautofagia/genética , Proteínas de la Membrana/genética , Procesamiento Postranscripcional del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Síndrome de Zellweger/genética , Síndrome de Zellweger/metabolismoRESUMEN
In Zellweger syndrome (ZS), lack of peroxisome function causes physiological and developmental abnormalities in many organs such as the brain, liver, muscles, and kidneys, but little is known about the exact pathogenic mechanism. By disrupting the zebrafish pex2 gene, we established a disease model for ZS and found that it exhibits pathological features and metabolic changes similar to those observed in human patients. By comprehensive analysis of the fatty acid profile, we found organ-specific accumulation and reduction of distinct fatty acid species, such as an accumulation of ultra-very-long-chain polyunsaturated fatty acids (ultra-VLC-PUFAs) in the brains of pex2 mutant fish. Transcriptome analysis using microarray also revealed mutant-specific gene expression changes that might lead to the symptoms, including reduction of crystallin, troponin, parvalbumin, and fatty acid metabolic genes. Our data indicated that the loss of peroxisomes results in widespread metabolic and gene expression changes beyond the causative peroxisomal function. These results suggest the genetic and metabolic basis of the pathology of this devastating human disease.
Asunto(s)
Ácidos Grasos/metabolismo , Expresión Génica , Peroxisomas/patología , Síndrome de Zellweger/genética , Síndrome de Zellweger/fisiopatología , Animales , Modelos Animales de Enfermedad , Ácidos Grasos/análisis , Ácidos Grasos/clasificación , Femenino , Perfilación de la Expresión Génica , Humanos , Hígado/patología , Masculino , Peroxinas/genética , Pez Cebra/genéticaRESUMEN
The incidence of rare diseases is approximately two cases per 10,000 people. Today, in most cases, orphan diseases are caused by genetic disorders, less often - some forms of oncological, oncohematological, infectious disorders. These conditions have a severe and chronic course, accompanied by a decrease in quality and a reduction in the life expectancy of patients. Aim - describe a clinical case of an rare disease that is referred to as Zellweger spectrum disorders. Literature review and analysis of clinical-anamnestic and laboratory-instrumental methods of research of a 6.5 years old girl. The given clinical case, namely Zellweger spectrum disorders (ZSD), is a hereditary autosomal recessive disease characterized by nonspecific clinical manifestations and phenotype, which complicates timely diagnosis and delays symptomatic, and in some cases prognostically favorable treatment. Molecular genetic research makes it possible to finally confirm this disease. Therefore, at the slightest suspicion of this pathology, it is worth investigating the level of long-chain fatty acids, plasmalogen of erythrocytes, intermediate metabolites of bile acid synthesis, or carrying out genetic sequencing. Further studies of this condition are carried out in the world in order to obtain new methods of treatment and improve the quality of life of patients. The presented clinical case of a rare disease, which belongs to ZSD, confirms the need for alertness of family doctors and pediatricians in order to timely diagnose and correct rare diseases in children.
Asunto(s)
Síndrome de Zellweger , Niño , Femenino , Humanos , Peroxisomas , Fenotipo , Calidad de Vida , Síndrome de Zellweger/genéticaRESUMEN
Zellweger spectrum disorders (ZSDs) are autosomal-recessive disorders that are caused by defects in peroxisome biogenesis due to bi-allelic mutations in any of 13 different PEX genes. Here, we identified seven unrelated individuals affected with an apparent dominant ZSD in whom a heterozygous mutant PEX6 allele (c.2578C>T [p.Arg860Trp]) was overrepresented due to allelic expression imbalance (AEI). We demonstrated that AEI of PEX6 is a common phenomenon and is correlated with heterozygosity for a frequent variant in the 3' untranslated region (UTR) of the mutant allele, which disrupts the most distal of two polyadenylation sites. Asymptomatic parents, who were heterozygous for PEX c.2578C>T, did not show AEI and were homozygous for the 3' UTR variant. Overexpression models confirmed that the overrepresentation of the pathogenic PEX6 c.2578T variant compared to wild-type PEX6 c.2578C results in a peroxisome biogenesis defect and thus constitutes the cause of disease in the affected individuals. AEI promoting the overrepresentation of a mutant allele might also play a role in other autosomal-recessive disorders, in which only one heterozygous pathogenic variant is identified.
Asunto(s)
Regiones no Traducidas 3'/genética , ATPasas Asociadas con Actividades Celulares Diversas/genética , Desequilibrio Alélico/genética , Síndrome de Zellweger/genética , Alelos , Células Cultivadas , Femenino , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Peroxisomas/genética , Peroxisomas/patología , Secuenciación del ExomaRESUMEN
BACKGROUND: Peroxisome biogenesis disorders (PBDs) are a group of metabolic diseases caused by dysfunction of peroxisomes. Different forms of PBDs are described; the most severe one is the Zellweger syndrome (ZS). We report on an unusual presentation of Zellweger syndrome manifesting in a newborn with severe and fulminant sepsis, causing death during the neonatal period. CASE PRESENTATION: A term male Caucasian neonate presented at birth with hypotonia and poor feeding associated with dysmorphic craniofacial features and skeletal abnormalities. Blood tests showed progressive leukopenia; ultrasounds revealed cerebral and renal abnormalities. He died on the fourth day of life because of an irreversible Gram-negative sepsis. Post-mortem tests on blood and urine samples showed biochemical alterations suggestive of ZS confirmed by genetic test. CONCLUSIONS: ZS is an early and severe forms of PBDs. Peroxisomes are known to be involved in lipid metabolism, but recent studies suggest their fundamental role in modulating immune response and inflammation. In case of clinical suspicion of ZS it is important to focus the attention on the prevention and management of infections that can rapidly progress to death.
Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/genética , Infecciones por Bacterias Gramnegativas/genética , Mutación , Peroxisomas/inmunología , Sepsis/genética , Síndrome de Zellweger/genética , ATPasas Asociadas con Actividades Celulares Diversas/deficiencia , ATPasas Asociadas con Actividades Celulares Diversas/inmunología , Resultado Fatal , Expresión Génica , Infecciones por Bacterias Gramnegativas/inmunología , Infecciones por Bacterias Gramnegativas/microbiología , Infecciones por Bacterias Gramnegativas/patología , Humanos , Inmunidad Innata , Recién Nacido , Masculino , Peroxisomas/microbiología , Peroxisomas/patología , Sepsis/inmunología , Sepsis/microbiología , Sepsis/patología , Síndrome de Zellweger/inmunología , Síndrome de Zellweger/microbiología , Síndrome de Zellweger/patologíaRESUMEN
Purpose: The aim of the present work is the molecular diagnosis of three patients with deafness and retinal degeneration. Methods: Three patients from two unrelated families were initially analyzed with custom gene panels for Usher genes, non-syndromic hearing loss, or inherited syndromic retinopathies and further investigated by means of clinical or whole exome sequencing. Results: The study allowed us to detect likely pathogenic variants in PEX6, a gene typically involved in peroxisomal biogenesis disorders (PBDs). Beside deaf-blindness, both families showed additional features: Siblings from Family 1 showed enamel alteration and abnormal peroxisome. In addition, the brother had mild neurodevelopmental delay and nephrolithiasis. The case II:1 from Family 2 showed intellectual disability, enamel alteration, and dysmorphism. Conclusions: We have reported three new cases with pathogenic variants in PEX6 presenting with milder forms of the Zellweger spectrum disorders (ZSD). The three cases showed distinct clinical features. Thus, expanding the phenotypic spectrum of PBDs and ascertaining exome sequencing is an effective strategy for an accurate diagnosis of clinically overlapping and genetically heterogeneous disorders such as deafness-blindness association.
Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/genética , Pérdida Auditiva Sensorineural/genética , Retinitis Pigmentosa/genética , Síndrome de Zellweger/genética , Adulto , Niño , Anomalías Craneofaciales/genética , Esmalte Dental/anomalías , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Mutación , Nefrolitiasis/genética , Trastornos del Neurodesarrollo/genética , Linaje , Peroxisomas/genética , Peroxisomas/metabolismo , Peroxisomas/patología , Secuenciación del ExomaRESUMEN
Zellweger syndrome disorders (ZSD) is the principal group of peroxisomal disorders characterized by a defect of peroxisome biogenesis due to mutations in one of the 13 PEX genes. The clinical spectrum is very large with a continuum from antenatal forms to adult presentation. Whereas biochemical profile in body fluids is classically used for their diagnosis, the revolution of high-throughput sequencing has extended the knowledge about these disorders. The aim of this review is to offer a large panorama on molecular basis, clinical presentation and treatment of ZSD, and to update the diagnosis strategy of these disorders in the era of next-generation sequencing (NGS).
Asunto(s)
Enfermedades del Recién Nacido , Síndrome de Zellweger , Adulto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Recién Nacido , Enfermedades del Recién Nacido/diagnóstico , Enfermedades del Recién Nacido/genética , Enfermedades del Recién Nacido/patología , Mutación , Peroxisomas/metabolismo , Peroxisomas/patología , Síndrome de Zellweger/diagnóstico , Síndrome de Zellweger/genética , Síndrome de Zellweger/patologíaRESUMEN
Peroxisomal D-bifunctional protein (DBP), encoded by the HSD17B4 gene, catalyzes ß-oxidation of very long chain fatty acids (VLCFAs). The deficiency of this peroxisomal enzyme leads to the accumulation of VLCFAs, causing multisystemic manifestations including the brain, retina, adrenal gland, hearing, and skeletal system. Herein, we report the first Korean neonatal case of peroxisomal DBP deficiency and the clinical prognosis over 2 years. This patient showed craniofacial dysmorphism, club foot, and seizures with cyanosis one day after birth. Elevated VLCFAs levels were indicative of a peroxisomal disorder. Targeted exome sequencing was performed and two missense mutations p.Asp117Val and p.Phe279Ser in the HSD17B4 gene were identified. The patient had type III DBP deficiency; therefore, docosahexaenoic acid and non-soluble vitamins were administered. However, progressive nystagmus, optic nerve atrophy, and bilateral hearing defects were observed and follow-up brain imaging revealed leukodystrophy and brain atrophy. Multiple anti-epileptic drugs were required to control the seizures. Over two years, the patient achieved normal growth with home ventilation and tube feeding. Hereby, the subject's parents had support during the second pregnancy from the proven molecular information. Moreover, targeted exome sequencing is an effective diagnostic approach, considering genetic heterogeneity of Zellweger spectrum disorders.
Asunto(s)
Proteína-2 Multifuncional Peroxisomal/genética , Síndrome de Zellweger/diagnóstico , Encéfalo/diagnóstico por imagen , Femenino , Heterocigoto , Humanos , Recién Nacido , Imagen por Resonancia Magnética , Mutación Missense , Linaje , Proteína-2 Multifuncional Peroxisomal/deficiencia , República de Corea , Convulsiones/diagnóstico , Convulsiones/etiología , Síndrome de Zellweger/genéticaRESUMEN
PURPOSE: We aimed to estimate the carrier frequency of Zellweger spectrum disorder (ZSD), a rare autosomal recessive disease, and the associated disease incidence based on data from the Exome Aggregation Consortium (ExAC) of approximately 60,000 individuals. METHODS: We obtained variants from ExAC in 13 PEX genes associated with ZSD. Potentially pathogenic missense variants were identified with computational variant analysis tools according to three stringency levels. Using variants classified as potentially pathogenic, we estimated the carrier frequency and the associated incidence for the entire ExAC population and its subpopulations. We also evaluated variants based on pathogenicity criteria for sequence variant interpretation outlined by the American College of Medical Genetics and Genomics (ACMG) and calculated the carrier frequency and incidence based on those variants. RESULTS: The bioinformatically estimated incidence rate of ZSD in the ExAC population is 1 in 83,841 using our least stringent pathogenicity cutoff. Under clinical guidelines outlined by ACMG, the estimated incidence is 1 in 3,275,751 births. CONCLUSION: We outlined a process for estimating the ZSD disease carrier frequency and incidence in a large consortium using bioinformatics tools. Our results are close to current newborn screening estimates in New York of 1 in 90,000 births, estimated from 1.08 million screenings.
Asunto(s)
Exoma/genética , Tamización de Portadores Genéticos/métodos , Predisposición Genética a la Enfermedad , Síndrome de Zellweger/diagnóstico , Biología Computacional , Bases de Datos Genéticas , Variación Genética , Humanos , Recién Nacido , Mutación , Tamizaje Neonatal/métodos , Síndrome de Zellweger/epidemiología , Síndrome de Zellweger/genéticaRESUMEN
PEX13 is an integral membrane protein on the peroxisome that regulates peroxisomal matrix protein import during peroxisome biogenesis. Mutations in PEX13 and other peroxin proteins are associated with Zellweger syndrome spectrum (ZSS) disorders, a subtype of peroxisome biogenesis disorder characterized by prominent neurological, hepatic, and renal abnormalities leading to neonatal death. The lack of functional peroxisomes in ZSS patients is widely accepted as the underlying cause of disease; however, our understanding of disease pathogenesis is still incomplete. Here, we demonstrate that PEX13 is required for selective autophagy of Sindbis virus (virophagy) and of damaged mitochondria (mitophagy) and that disease-associated PEX13 mutants I326T and W313G are defective in mitophagy. The mitophagy function of PEX13 is shared with another peroxin family member PEX3, but not with two other peroxins, PEX14 and PEX19, which are required for general autophagy. Together, our results demonstrate that PEX13 is required for selective autophagy, and suggest that dysregulation of PEX13-mediated mitophagy may contribute to ZSS pathogenesis.