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BACKGROUND: Based on a limited number of reported families, biallelic CA8 variants have currently been associated with a recessive neurological disorder named, cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CAMRQ-3). OBJECTIVES: We aim to comprehensively investigate CA8-related disorders (CA8-RD) by reviewing existing literature and exploring neurological, neuroradiological, and molecular observations in a cohort of newly identified patients. METHODS: We analyzed the phenotype of 27 affected individuals from 14 families with biallelic CA8 variants (including data from 15 newly identified patients from eight families), ages 4 to 35 years. Clinical, genetic, and radiological assessments were performed, and zebrafish models with ca8 knockout were used for functional analysis. RESULTS: Patients exhibited varying degrees of neurodevelopmental disorders (NDD), along with predominantly progressive cerebellar ataxia and pyramidal signs and variable bradykinesia, dystonia, and sensory impairment. Quadrupedal gait was present in only 10 of 27 patients. Progressive selective cerebellar atrophy, predominantly affecting the superior vermis, was a key diagnostic finding in all patients. Seven novel homozygous CA8 variants were identified. Zebrafish models demonstrated impaired early neurodevelopment and motor behavior on ca8 knockout. CONCLUSION: Our comprehensive analysis of phenotypic features indicates that CA8-RD exhibits a wide range of clinical manifestations, setting it apart from other subtypes within the category of CAMRQ. CA8-RD is characterized by cerebellar atrophy and should be recognized as part of the autosomal-recessive cerebellar ataxias associated with NDD. Notably, the presence of progressive superior vermis atrophy serves as a valuable diagnostic indicator. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Ataxia Cerebelar , Peixe-Zebra , Humanos , Ataxia Cerebelar/genética , Criança , Adolescente , Masculino , Feminino , Pré-Escolar , Animais , Adulto , Adulto Jovem , Anoctaminas/genética , Deficiência Intelectual/genética , Fenótipo , Transtornos do Neurodesenvolvimento/genéticaRESUMO
We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.
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Deficiências do Desenvolvimento/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Degradação do RNAm Mediada por Códon sem Sentido , Adolescente , Encéfalo/anormalidades , Criança , Pré-Escolar , Consanguinidade , Deficiências do Desenvolvimento/metabolismo , Saúde da Família , Feminino , Deleção de Genes , Ligação Genética , Cardiopatias Congênitas/genética , Homozigoto , Humanos , Lactente , Masculino , Linhagem , Fenótipo , Fosforilação , RNA Helicases/metabolismo , RNA Mensageiro/metabolismo , RNA-Seq , Transativadores/metabolismo , Adulto JovemRESUMO
INTRODUCTION: An increasing number of pediatric patients with inherited metabolic disorders are reaching adulthood. In addition, many patients are diagnosed for the first time in adult life due to improved awareness of these disorders and the availability of advanced diagnostic technology. Knowledge of these inherited metabolic disorders in adults is crucial for the emergency physician to promptly recognize their acute illness and appropriately manage them in the emergency department. OBJECTIVE: This review provides an overview of various inherited metabolic disorders which present to the emergency department with acute metabolic decompensation. EVALUATION AND MANAGEMENT: Acute illness in these patients is often triggered by a catabolic event such as intercurrent illness, fasting, postpartum, or use of certain medication. It may present in a variety of ways related to severe hyperammonemia, metabolic acidosis, leucine encephalopathy or hypoglycemia. In this review, we describe the clinical presentation, evaluation and immediate management of their critical illness in the emergency department. CONCLUSION: Acute metabolic decompensation is a life-threatening condition. The emergency physician is usually the first provider to evaluate these patients when they present to the emergency department. Early recognition of their illness and prompt management of these cases improve patient outcomes.
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Acidose , Hiperamonemia , Hipoglicemia , Acidose/diagnóstico , Doença Aguda , Adulto , Criança , Estado Terminal/terapia , Feminino , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/terapiaRESUMO
Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects' cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis.
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The dysfunction of microtubules (α/ß-tubulin polymers) underlies a wide range of nervous system genetic abnormalities. Defects in TBCD, a tubulin-folding cofactor, cause diseases highlighted with early-onset encephalopathy with or without neurodegeneration, intellectual disability, seizures, microcephaly and tetraparaperesis. Utilizing various molecular methods, we describe nine patients from four unrelated families with two novel exon 18 variants in TBCD exhibiting the typical neurological phenotype of the disease. Interestingly, all the investigated patients had previously unreported hematological findings in the form of neutropenia and mild degree of anemia and thrombocytopenia. In addition to delineating the neurological phenotype in several patients with TBCD variants, our study stresses on the new association of neutropenia, in particular, with the disease.
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Encefalopatias/sangue , Encefalopatias/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação de Sentido Incorreto , Adulto , Anemia/etiologia , Encefalopatias/complicações , Encefalopatias/diagnóstico por imagem , Criança , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Neutropenia/etiologia , Linhagem , Trombocitopenia/etiologia , Adulto JovemRESUMO
Pycnodysostosis is characterized by short stature, osteosclerosis, acro-osteolysis, increased tendency of fractures, and distinctive dysmorphic features. It is a rare autosomal recessive disease caused by biallelic CTSK mutations. The clinical details of 18 patients from Saudi Arabia were reviewed. Short stature, osteopetrosis, acro-osteolysis, and distinctive facial dysmorphism were documented in all cases. Our results highlight the significant complications associated with this disease. The large anterior fontanelle is one of the cardinal signs of this disease; however, half of our patients had small fontanelles and a quarter had craniosynostosis, which caused optic nerve compression. Sleep apnea was of the major complications in three patients. Bone fracture can be a presenting symptom, and in our patients it mainly occurred after the age of 3 years. Bone marrow suppression was seen in a single patient of our cohort who was misdiagnosed initially with malignant osteopetrosis. In this study, we also describe two novel (c.5G > A [p.Trp2Ter], c.538G > A [p.Gly180Ser]) and two reported (c.244-29 A > G, c.830C > T [p.Ala277Val]) CTSK mutations. Our results indicate that the recurrent intronic variant, c.244-29 A > G is likely to be a founder mutation, as it was found in 78% (14/18 patients) of our cohort belonging to the same tribe.
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Alelos , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Fenótipo , Picnodisostose/diagnóstico , Picnodisostose/genética , Catepsina K/genética , Pré-Escolar , Consanguinidade , Fácies , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Imageamento Tridimensional , Masculino , Mutação , Linhagem , Radiografia , Arábia Saudita , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: Ciliopathies are highly heterogeneous clinical disorders of the primary cilium. We aim to characterize a large cohort of ciliopathies phenotypically and molecularly. METHODS: Detailed phenotypic and genomic analysis of patients with ciliopathies, and functional characterization of novel candidate genes. RESULTS: In this study, we describe 125 families with ciliopathies and show that deleterious variants in previously reported genes, including cryptic splicing variants, account for 87% of cases. Additionally, we further support a number of previously reported candidate genes (BBIP1, MAPKBP1, PDE6D, and WDPCP), and propose nine novel candidate genes (CCDC67, CCDC96, CCDC172, CEP295, FAM166B, LRRC34, TMEM17, TTC6, and TTC23), three of which (LRRC34, TTC6, and TTC23) are supported by functional assays that we performed on available patient-derived fibroblasts. From a phenotypic perspective, we expand the phenomenon of allelism that characterizes ciliopathies by describing novel associations including WDR19-related Stargardt disease and SCLT1- and CEP164-related Bardet-Biedl syndrome. CONCLUSION: In this cohort of phenotypically and molecularly characterized ciliopathies, we draw important lessons that inform the clinical management and the diagnostics of this class of disorders as well as their basic biology.
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Síndrome de Bardet-Biedl , Ciliopatias , Alelos , Síndrome de Bardet-Biedl/genética , Cílios/genética , Ciliopatias/genética , Humanos , Canais de SódioRESUMO
Hearing loss (HL) is the most common sensory disorder worldwide and genetic factors contribute to approximately half of congenital HL cases. HL is subject to extensive genetic heterogeneity, rendering molecular diagnosis difficult. Mutations of the transmembrane channel-like 1 (TMC1) gene cause hearing defects in humans and mice. The precise function of TMC1 protein in the inner ear is unknown, although it is predicted to be involved in functional maturation of cochlear hair cells. TMC1 mutations result in autosomal recessive (DFNB7/11) and sometimes dominant (DFNA36) nonsyndromic HL. Mutations in TMC1 are responsible for a significant portion of HL, particularly in consanguineous populations. To evaluate the importance of TMC1 mutations in the Saudi population, we used a combination of autozygome-guided candidate gene mutation analysis and targeted next generation sequencing in 366 families with HL previously shown to lack mutations in GJB2. We identified 12 families that carried five causative TMC1 mutations; including three novel (c.362+3A > G; c.758C > T [p.Ser253Phe]; c.1396_1398delACC [p.Asn466del]) and two reported mutations (c.100C > T [p.Arg34Ter]; c.1714G > A [p.Asp572Asn]). Each of the identified recessive mutation was classified as severe, by both age of onset and severity of HL. Similarly, consistent with the previously reported dominant variant p.Asp572Asn, the HL phenotype was progressive. Eight families in our cohort were found to share the pathogenic p.Arg34Ter mutation and linkage disequilibrium was observed between p.Arg34Ter and SNPs investigated. Our results indicate that TMC1 mutations account for about 3.3% (12/366) of Saudi HL cases and that the recurrent TMC1 mutation p.Arg34Ter is likely to be a founder mutation.
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Perda Auditiva Neurossensorial/genética , Proteínas de Membrana/genética , Mutação , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Análise Mutacional de DNA , Orelha Interna/metabolismo , Éxons , Saúde da Família , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Arábia Saudita , Adulto JovemRESUMO
The tRNA splicing endonuclease is a highly evolutionarily conserved protein complex, involved in the cleavage of intron-containing tRNAs. In human it consists of the catalytic subunits TSEN2 and TSEN34, as well as the non-catalytic TSEN54 and TSEN15. Recessive mutations in the corresponding genes of the first three are known to cause pontocerebellar hypoplasia (PCH) types 2A-C, 4, and 5. Here, we report three homozygous TSEN15 variants that cause a milder version of PCH2. The affected individuals showed progressive microcephaly, delayed developmental milestones, intellectual disability, and, in two out of four cases, epilepsy. None, however, displayed the central visual failure seen in PCH case subjects where other subunits of the TSEN are mutated, and only one was affected by the extensive motor defects that are typical in other forms of PCH2. The three amino acid substitutions impacted the protein level of TSEN15 and the stoichiometry of the interacting subunits in different ways, but all resulted in an almost complete loss of in vitro tRNA cleavage activity. Taken together, our results demonstrate that mutations in any known subunit of the TSEN complex can cause PCH and progressive microcephaly, emphasizing the importance of its function during brain development.
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Doenças Cerebelares/genética , Endonucleases/genética , Genes Recessivos , Microcefalia/genética , Mutação , Sequência de Aminoácidos , Criança , Pré-Escolar , Endonucleases/química , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Modelos Moleculares , LinhagemRESUMO
BACKGROUND: Pulmonary fibrosis is one of the leading indications for lung transplantation. The disease, which is of unknown aetiology, can be progressive, resulting in distortion of the extracellular matrix (ECM), inflammation, fibrosis and eventual death. METHODS: 13 patients born to consanguineous parents from two unrelated families presenting with interstitial lung disease were clinically investigated. Nine patients developed respiratory failure and subsequently died. Molecular genetic investigations were performed on patients' whole blood or archived tissues, and cell biological investigations were performed on patient-derived fibroblasts. RESULTS: The combination of a unique pattern of early-onset lung fibrosis (at 12-15â years old) with distinctive radiological findings, including 1) traction bronchiectasis, 2) intralobular septal thickening, 3) shrinkage of the secondary pulmonary lobules mainly around the bronchovascular bundles and 4) early type 2 respiratory failure (elevated blood carbon dioxide levels), represents a novel clinical subtype of familial pulmonary fibrosis. Molecular genetic investigation of families revealed a hypomorphic variant in S100A3 and a novel truncating mutation in S100A13, both segregating with the disease in an autosomal recessive manner. Family members that were either heterozygous carriers or wild-type normal for both variants were unaffected. Analysis of patient-derived fibroblasts demonstrated significantly reduced S100A3 and S100A13 expression. Further analysis demonstrated aberrant intracellular calcium homeostasis, mitochondrial dysregulation and differential expression of ECM components. CONCLUSION: Our data demonstrate that digenic inheritance of mutations in S100A3 and S100A13 underlie the pathophysiology of pulmonary fibrosis associated with a significant reduction of both proteins, which suggests a calcium-dependent therapeutic approach for management of the disease.
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Pulmão/patologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/fisiopatologia , Proteínas S100/genética , Adolescente , Criança , Saúde da Família , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Mutação , Linhagem , Fibrose Pulmonar/diagnóstico , Arábia SauditaRESUMO
PURPOSE: Wolf-Hirschhorn syndrome (WHS) is a genomic disorder with a recognizable dysmorphology profile caused by hemizygosity at 4p16.3. Previous attempts have failed to map the minimal critical locus to a single gene, leaving open the possibility that the core phenotypic components of the syndrome are caused by the combined haploinsufficiency of multiple genes. METHODS: Clinical exome sequencing and "reverse" phenotyping. RESULTS: We identified two patients with de novo truncating variants in WHSC1, which maps to the WHS critical locus. The phenotype of these two individuals is consistent with WHS, which suggests that haploinsufficiency of WHSC1 is sufficient to recapitulate the core phenotype (characteristic facies, and growth and developmental delay) of this classic microdeletion syndrome. CONCLUSION: Our study expands the list of microdeletion syndromes that are solved at the single-gene level, and establishes WHSC1 as a disease gene in humans. Given the severe nature of the reported variants, the full phenotypic expression of WHSC1 may be further expanded by future reports of milder variants.
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Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Histona-Lisina N-Metiltransferase/genética , Proteínas Repressoras/genética , Síndrome de Wolf-Hirschhorn/genética , Pré-Escolar , Deleção Cromossômica , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/patologia , Feminino , Haploinsuficiência/genética , Humanos , Masculino , Fenótipo , Síndrome de Wolf-Hirschhorn/diagnóstico , Síndrome de Wolf-Hirschhorn/patologiaRESUMO
PURPOSE: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. METHODS: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. RESULTS: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. CONCLUSION: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.
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Microcefalia/genética , Microcefalia/fisiopatologia , Adulto , Criança , Pré-Escolar , Nanismo/genética , Feminino , Genômica/métodos , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Mutação/genética , Linhagem , Fenótipo , Sequenciamento do Exoma/métodosRESUMO
PURPOSE: Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases. METHODS: Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders. CONCLUSIONS: Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.
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Doença/genética , Genômica/métodos , Análise de Sequência de DNA/métodos , Variação Biológica da População/genética , Criança , Pré-Escolar , Diagnóstico , Técnicas e Procedimentos Diagnósticos , Feminino , Testes Genéticos/normas , Variação Genética , Genótipo , Hereditariedade/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , FenótipoRESUMO
Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease-causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population ~1:30 000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend toward genotype/phenotype correlation in terms of long-term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond 1 year of age. Most unusual among the long-term survivors was a multiplex family in which the affected members presented as adults with non-specific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl-CoA reductase 1 disorder as well as CRD, spastic paraparesis, white matter (CRSPW) syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the "gold standard" very long chain fatty acids assay, which highlights the value of a genomics-first approach in these cases.
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Árabes , Transtornos Peroxissômicos/epidemiologia , Transtornos Peroxissômicos/etiologia , Árabes/genética , Biomarcadores , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Estudos de Coortes , Consanguinidade , Efeitos Psicossociais da Doença , Gerenciamento Clínico , Suscetibilidade a Doenças , Fácies , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutação , Linhagem , Transtornos Peroxissômicos/diagnóstico , Transtornos Peroxissômicos/terapia , Fenótipo , Vigilância da População , PrognósticoRESUMO
Acyl-CoA binding domain-containing 5 (ACBD5) is a peroxisomal protein that carries an acyl-CoA binding domain (ACBD) at its N-terminal region. The recent identification of a mutation in the ACBD5 gene in patients with a syndromic form of retinal dystrophy highlights the physiological importance of ACBD5 in humans. However, the underlying pathogenic mechanisms and the precise function of ACBD5 remain unclear. We herein report that ACBD5 is a peroxisomal tail-anchored membrane protein exposing its ACBD to the cytosol. Using patient-derived fibroblasts and ACBD5 knock-out HeLa cells generated via genome editing, we demonstrate that ACBD5 deficiency causes a moderate but significant defect in peroxisomal ß-oxidation of very-long-chain fatty acids (VLCFAs) and elevates the level of cellular phospholipids containing VLCFAs without affecting peroxisome biogenesis, including the import of membrane and matrix proteins. Both the N-terminal ACBD and peroxisomal localization of ACBD5 are prerequisite for efficient VLCFA ß-oxidation in peroxisomes. Furthermore, ACBD5 preferentially binds very-long-chain fatty acyl-CoAs (VLC-CoAs). Together, these results suggest a direct role of ACBD5 in peroxisomal VLCFA ß-oxidation. Based on our findings, we propose that ACBD5 captures VLC-CoAs on the cytosolic side of the peroxisomal membrane so that the transport of VLC-CoAs into peroxisomes and subsequent ß-oxidation thereof can proceed efficiently. Our study reclassifies ACBD5-related phenotype as a novel peroxisomal disorder.
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Acil Coenzima A/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Citosol/metabolismo , Ácidos Graxos/metabolismo , Proteínas de Membrana/metabolismo , Peroxissomos/metabolismo , Acil Coenzima A/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Transporte Biológico Ativo/genética , Ácidos Graxos/genética , Células HeLa , Humanos , Proteínas de Membrana/genética , Oxirredução , Peroxissomos/genética , Peroxissomos/patologia , Domínios Proteicos , Coelhos , Distrofias Retinianas/genética , Distrofias Retinianas/metabolismo , Distrofias Retinianas/patologiaRESUMO
This corrects the article DOI: 10.1038/gim.2017.22.
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OBJECTIVE: Autosomal recessive primary microcephaly (MCPH) is a rare condition characterized by a reduced cerebral cortex accompanied with intellectual disability. Mutations in 17 genes have been shown to cause this phenotype. Recently, mutations in CIT, encoding CRIK (citron rho-interacting kinase)-a component of the central spindle matrix-were added. We aimed at identifying novel MCPH-associated genes and exploring their functional role in pathogenesis. METHODS: Linkage analysis and whole exome sequencing were performed in consanguineous and nonconsanguineous MCPH families to identify disease-causing variants. Functional consequences were investigated by RNA studies and on the cellular level using immunofluorescence and microscopy. RESULTS: We identified homozygous mutations in KIF14 (NM_014875.2;c.263T>A;pLeu88*, c.2480_2482delTTG; p.Val827del, and c.4071G>A;p.Gln1357=) as the likely cause in 3 MCPH families. Furthermore, in a patient presenting with a severe form of primary microcephaly and short stature, we identified compound heterozygous missense mutations in KIF14 (NM_014875.2;c.2545C>G;p.His849Asp and c.3662G>T;p.Gly1221Val). Three of the 5 identified mutations impaired splicing, and 2 resulted in a truncated protein. Intriguingly, Kif14 knockout mice also showed primary microcephaly. Human kinesin-like protein KIF14, a microtubule motor protein, localizes at the midbody to finalize cytokinesis by interacting with CRIK. We found impaired localization of both KIF14 and CRIK at the midbody in patient-derived fibroblasts. Furthermore, we observed a large number of binucleated and apoptotic cells-signs of failed cytokinesis that we also observed in experimentally KIF14-depleted cells. INTERPRETATION: Our data corroborate the role of an impaired cytokinesis in the etiology of primary and syndromic microcephaly, as has been proposed by recent findings on CIT mutations. Ann Neurol 2017;82:562-577.
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Citocinese/genética , Regulação da Expressão Gênica/genética , Cinesinas/genética , Microcefalia/genética , Mutação/genética , Proteínas Oncogênicas/genética , Caspase 7/metabolismo , Movimento Celular/genética , Células Cultivadas , Criança , Pré-Escolar , Saúde da Família , Feminino , Fibroblastos/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Tubulina (Proteína)/metabolismoRESUMO
OBJECTIVE: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. METHODS: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. RESULTS: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. INTERPRETATION: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.
Assuntos
Hidrolases de Éster Carboxílico/genética , Surdocegueira/diagnóstico por imagem , Surdocegueira/genética , Progressão da Doença , Distonia/diagnóstico por imagem , Distonia/genética , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Mutação/genética , Atrofia Óptica/diagnóstico por imagem , Atrofia Óptica/genética , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Surdocegueira/terapia , Distonia/terapia , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/terapia , Masculino , Atrofia Óptica/terapia , Adulto JovemRESUMO
Patients with isolated methylmalonic acidemia (MMA) may present with a wide range of hematological complications including anemia, leukopenia, thrombocytopenia, and pancytopenia. However, there are very limited data on the development of hemophagocytosis or myelodysplasia in these patients. We report three patients with isolated MUT related MMA who presented with severe refractory pancytopenia during acute illness. Their bone marrow examination revealed a wide spectrum of pathology varying from bone marrow hypoplasia, hemophagocytosis to myelodysplasia with ring sideroblasts. We discuss their management and outcome. This report emphasizes the need for bone marrow examination in these patients with refractory or unexplained severe cytopenia, to confirm bone marrow pathology, and to rule out other diseases with similar clinical presentation for a better clinical outcome.