RESUMO
Mitochondrial fission and fusion are vital dynamic processes for mitochondrial quality control and for the maintenance of cellular respiration; they also play an important role in the formation and maintenance of cells with high energy demand including cardiomyocytes and neurons. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family that is responsible for the fission of mitochondria; it is ubiquitous but highly expressed in the developing neonatal heart. De novo heterozygous pathogenic variants in the DNM1L gene have been previously reported to be associated with neonatal or infantile-onset encephalopathy characterized by hypotonia, developmental delay and refractory epilepsy. However, cardiac involvement has been previously reported only in one case. Next-Generation Sequencing (NGS) was used to genetically assess a baby girl characterized by developmental delay with spastic-dystonic, tetraparesis and hypertrophic cardiomyopathy of the left ventricle. Histochemical analysis and spectrophotometric determination of electron transport chain were performed to characterize the muscle biopsy; moreover, the morphology of mitochondria and peroxisomes was evaluated in cultured fibroblasts as well. Herein, we expand the phenotype of DNM1L-related disorder, describing the case of a girl with a heterozygous mutation in DNM1L and affected by progressive infantile encephalopathy, with cardiomyopathy and fatal paroxysmal vomiting correlated with bulbar transitory abnormal T2 hyperintensities and diffusion-weighted imaging (DWI) restriction areas, but without epilepsy. In patients with DNM1L mutations, careful evaluation for cardiac involvement is recommended.
Assuntos
Cardiomiopatias , Dinaminas , Mutação , Humanos , Feminino , Dinaminas/genética , Cardiomiopatias/genética , Mutação/genética , Lactente , Evolução Fatal , Encefalopatias/genética , Encefalopatias/patologia , GTP Fosfo-Hidrolases/genéticaRESUMO
AFG3-like matrix AAA peptidase subunit 2 gene (AFG3L2, OMIM * 604,581) biallelic mutations lead to autosomal recessive spastic ataxia-5 SPAX5, OMIM # 614,487), a rare hereditary form of ataxia. The clinical spectrum includes early-onset cerebellar ataxia, spasticity, and progressive myoclonic epilepsy (PME). In Italy, the epidemiology of the disease is probably underestimated. The advent of next generation sequencing (NGS) technologies has speeded up the diagnosis of hereditary diseases and increased the percentage of diagnosis of rare disorders, such as the rare hereditary ataxia groups. Here, we describe two patients from two different villages in the province of Ferrara, who manifested a different clinical ataxia-plus history, although carrying the same biallelic mutation in AFG3L2 (p.Met625Ile) identified through NGS analysis.
Assuntos
Ataxia Cerebelar , Degenerações Espinocerebelares , Humanos , ATPases Associadas a Diversas Atividades Celulares/genética , Degenerações Espinocerebelares/genética , Ataxia Cerebelar/genética , Mutação/genética , Itália , Proteases Dependentes de ATP/genéticaRESUMO
OBJECTIVE: Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. METHODS: We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts. RESULTS: Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. INTERPRETATION: This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18-32.
Assuntos
Proteases Dependentes de ATP/genética , ATPases Associadas a Diversas Atividades Celulares/genética , GTP Fosfo-Hidrolases/genética , Atrofia Óptica/genética , Doenças do Nervo Óptico/genética , Adolescente , Adulto , Idoso , Criança , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Sequenciamento do Exoma , Adulto JovemRESUMO
A 60-year-old man is presented with progressive involuntary muscle movements and neuropsychiatric symptoms who developed a variety of additional complaints over 2 years. Brain imaging revealed bilateral basal ganglia calcifications suggesting primary familial brain calcification. Analysis of the SLC20A2 gene revealed a missense mutation (c.541C>T, p.(Arg181Trp)), in silico predicted to be deleterious and not found in available databases. Segregation analysis confirmed his asymptomatic father to harbor the same mutation, though on brain imaging basal ganglia calcifications were found. This report illustrates the intrafamilial variability of the phenotype and generalized myoclonus as the presenting symptom.
Assuntos
Calcinose/genética , Mioclonia/genética , Doenças Neurodegenerativas/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/etiologia , Mutação de Sentido Incorreto , Doenças Neurodegenerativas/patologia , LinhagemRESUMO
Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family, responsible for fission of mitochondria, and having a role in the division of peroxisomes, as well. DRP1 impairment is implicated in several neurological disorders and associated with either de novo dominant or compound heterozygous mutations. In five patients presenting with severe epileptic encephalopathy, we identified five de novo dominant DNM1L variants, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. Moreover, a very peculiar finding in our cohort of patients was the presence, in muscle biopsy, of core like areas with oxidative enzyme alterations, suggesting an abnormal distribution of mitochondria in the muscle tissue.
Assuntos
Dinaminas/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Encefalomiopatias Mitocondriais/diagnóstico , Encefalomiopatias Mitocondriais/genética , Músculos/metabolismo , Músculos/patologia , Biomarcadores , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Análise Mutacional de DNA , Dinaminas/química , Fibroblastos/metabolismo , Estudos de Associação Genética/métodos , Humanos , Imageamento por Ressonância Magnética/métodos , Modelos Biológicos , Músculos/ultraestrutura , Mutação , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Here we report on a singleton patient affected by a complicated congenital syndrome characterized by growth delay, retinal dystrophy, sensorineural deafness, myopathy, ataxia, combined pituitary hormone deficiency, associated with mitochondrial impairment. Targeted clinical exome sequencing led to the identification of a homozygous missense variant in OTX2. Since only dominant mutations within OTX2 have been associated with cases of syndromic microphthalmia, retinal dystrophy with or without pituitary dysfunctions, this represents the first report of an OTX2 recessive mutation. Part of the phenotype, including ataxia, myopathy and multiple mitochondrial respiratory chain defects, seemed not related to OTX2. Further analysis of next generation sequencing (NGS) data revealed additional candidate variants: a homozygous variant in LETM1, and heterozygous rare variants in AFG3L2 and POLG. All three genes encode mitochondrial proteins and the last two are known to be associated with ataxia, a neurological sign present also in the father of the proband. With our study, we aim to encourage the integration of NGS data with a detailed analysis of clinical description and family history in order to unravel composite genotypes sometimes associated with complicated phenotypes.
Assuntos
Ataxia/genética , Homozigoto , Hipopituitarismo/genética , Mitocôndrias/genética , Doenças Musculares/genética , Mutação , Fatores de Transcrição Otx/genética , Distrofias Retinianas/genética , Adulto , Idoso , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Ataxia/diagnóstico , DNA Mitocondrial , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Hipopituitarismo/diagnóstico , Cariotipagem , Masculino , Mitocôndrias/metabolismo , Doenças Musculares/diagnóstico , Fatores de Transcrição Otx/química , Linhagem , Fenótipo , Distrofias Retinianas/diagnósticoRESUMO
Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic.
Assuntos
Encefalopatias/genética , Calcinose/genética , Disfunção Cognitiva/genética , Variação Genética/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encefalopatias/fisiopatologia , Calcinose/fisiopatologia , Criança , Disfunção Cognitiva/fisiopatologia , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Fenótipo , Proteínas Proto-Oncogênicas c-sis/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Virais/efeitos dos fármacos , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Receptor do Retrovírus Politrópico e Xenotrópico , Adulto JovemRESUMO
BACKGROUND: KARS encodes lysyl- transfer ribonucleic acid (tRNA) synthetase, which catalyzes the aminoacylation of tRNA-Lys in the cytoplasm and mitochondria. Eleven families/sporadic patients and 16 different mutations in KARS have been reported to date. The associated clinical phenotype is heterogeneous ranging from early onset encephalopathy to isolated peripheral neuropathy or nonsyndromic hearing impairment. Recently additional presentations including leukoencephalopathy as predominant cerebral involvement or cardiomyopathy, isolated or associated with muscular and cerebral involvement, have been reported. A progressive Leukoencephalopathy with brainstem and spinal cord calcifications was previously described in a singleton patient and in two siblings, without the identification of the genetic cause. We reported here about a new severe phenotype associated with biallelic KARS mutations and sharing some common points with the other already reported phenotypes, but with a distinct clinical and neuroimaging picture. Review of KARS mutant patients published to date will be also discussed. RESULTS: Herein, we report the clinical, biochemical and molecular findings of 2 unreported Italian patients affected by developmental delay, acquired microcephaly, spastic tetraparesis, epilepsy, sensory-neural hypoacusia, visual impairment, microcytic hypochromic anaemia and signs of hepatic dysfunction. MRI pattern in our patients was characterized by progressive diffuse leukoencephalopathy and calcifications extending in cerebral, brainstem and cerebellar white matter, with spinal cord involvement. Genetic analysis performed on these 2 patients and in one subject previously described with similar MRI pattern revealed the presence of biallelic mutations in KARS in all 3 subjects. CONCLUSIONS: With our report we define the molecular basis of the previously described Leukoencephalopathy with Brainstem and Spinal cord Calcification widening the spectrum of KARS related disorders, particularly in childhood onset disease suggestive for mitochondrial impairment. The review of previous cases does not suggest a strict and univocal genotype/phenotype correlation for this highly heterogeneous entity. Moreover, our cases confirm the usefulness of search for common brain and spine MR imaging pattern and of broad genetic screening, in syndromes clinically resembling mitochondrial disorders in spite of normal biochemical assay.
Assuntos
Tronco Encefálico/patologia , Calcinose/genética , Calcinose/patologia , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Lisina-tRNA Ligase/genética , Medula Espinal/patologia , Predisposição Genética para Doença , HumanosRESUMO
BACKGROUND: Hereditary myopathy with lactic acidosis and myopathy with deficiency of succinate dehydrogenase and aconitase are variants of a recessive disorder characterised by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, metabolic acidosis and rhabdomyolysis may occur. So far, this disease has been molecularly defined only in Swedish patients, all homozygous for a deep intronic splicing affecting mutation in ISCU encoding a scaffold protein for the assembly of iron-sulfur (Fe-S) clusters. A single Scandinavian family was identified with a different mutation, a missense change in compound heterozygosity with the common intronic mutation. The aim of the study was to identify the genetic defect in our proband. METHODS: A next-generation sequencing (NGS) approach was carried out on an Italian male who presented in childhood with ptosis, severe muscle weakness and exercise intolerance. His disease was slowly progressive, with partial recovery between episodes. Patient's specimens and yeast models were investigated. RESULTS: Histochemical and biochemical analyses on muscle biopsy showed multiple defects affecting mitochondrial respiratory chain complexes. We identified a single heterozygous mutation p.Gly96Val in ISCU, which was absent in DNA from his parents indicating a possible de novo dominant effect in the patient. Patient fibroblasts showed normal levels of ISCU protein and a few variably affected Fe-S cluster-dependent enzymes. Yeast studies confirmed both pathogenicity and dominance of the identified missense mutation. CONCLUSION: We describe the first heterozygous dominant mutation in ISCU which results in a phenotype reminiscent of the recessive disease previously reported.
Assuntos
Genes Dominantes , Proteínas Ferro-Enxofre/genética , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Mutação , Sequência de Aminoácidos , Biomarcadores , Biópsia , Biologia Computacional/métodos , Eletroencefalografia , Eletromiografia , Fibroblastos/metabolismo , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas Ferro-Enxofre/química , Imageamento por Ressonância Magnética , Masculino , Modelos Moleculares , Músculo Esquelético/patologia , Linhagem , Fenótipo , Análise de Sequência de DNA , Relação Estrutura-Atividade , Adulto JovemRESUMO
Patients with pathogenic truncating mutations in the prion gene (PRNP) usually present with prolonged disease courses with severe neurofibrillary tangle and cerebral amyloidosis pathology, but more atypical phenotypes also occur, including those with dysautonomia and peripheral neuropathy. We describe the neurological, cognitive, neuroimaging, and electrophysiological features of a 31-year-old man presenting with an orbitofrontal syndrome, gastrointestinal symptoms, and peripheral neuropathy associated with PRNP Q160X nonsense mutation, with symptom onset at age 27. The mutation was also detected in his asymptomatic father and a symptomatic paternal cousin; several members of prior generations died from early onset dementia. This is the first report of a family affected with the nonsense PRNP mutation Q160X displaying clear autosomal dominant disease in multiple family members and reduced penetrance. This case strengthens the evidence suggesting an association between PRNP truncating mutations and prion systemic amyloidosis. PRNP gene testing should be considered in any patient with atypical dementia, especially with early onset and neuropathy, even in the absence of a family history.
Assuntos
Códon sem Sentido , Doenças Priônicas/genética , Doenças Priônicas/fisiopatologia , Proteínas Priônicas/genética , Adulto , Encéfalo/diagnóstico por imagem , Progressão da Doença , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Linhagem , Nervos Periféricos/fisiopatologia , Fenótipo , Doenças Priônicas/diagnóstico por imagemAssuntos
Encefalopatias/genética , Calcinose/genética , Saúde da Família , Mutação/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Adulto , Idade de Início , Encefalopatias/complicações , Encefalopatias/diagnóstico por imagem , Calcinose/complicações , Calcinose/diagnóstico por imagem , Análise Mutacional de DNA , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Noruega , Tomógrafos ComputadorizadosRESUMO
This study focused on the molecular characterization of patients with leukoencephalopathy associated with a specific biochemical defect of mitochondrial respiratory chain complex III, and explores the impact of a distinct magnetic resonance imaging pattern of leukoencephalopathy to detect biallelic mutations in LYRM7 in patients with biochemically unclassified leukoencephalopathy. 'Targeted resequencing' of a custom panel including genes coding for mitochondrial proteins was performed in patients with complex III deficiency without a molecular genetic diagnosis. Based on brain magnetic resonance imaging findings in these patients, we selected additional patients from a database of unclassified leukoencephalopathies who were scanned for mutations in LYRM7 by Sanger sequencing. Targeted sequencing revealed homozygous mutations in LYRM7, encoding mitochondrial LYR motif-containing protein 7, in four patients from three unrelated families who had a leukoencephalopathy and complex III deficiency. Two subjects harboured previously unreported variants predicted to be damaging, while two siblings carried an already reported pathogenic homozygous missense change. Sanger sequencing performed in the second cohort of patients revealed LYRM7 mutations in three additional patients, who were selected on the basis of the magnetic resonance imaging pattern. All patients had a consistent magnetic resonance imaging pattern of progressive signal abnormalities with multifocal small cavitations in the periventricular and deep cerebral white matter. Early motor development was delayed in half of the patients. All patients but one presented with subacute neurological deterioration in infancy or childhood, preceded by a febrile infection, and most patients had repeated episodes of subacute encephalopathy with motor regression, irritability and stupor or coma resulting in major handicap or death. LYRM7 protein was strongly reduced in available samples from patients; decreased complex III holocomplex was observed in fibroblasts from a patient carrying a splice site variant; functional studies in yeast confirmed the pathogenicity of two novel mutations. Mutations in LYRM7 were previously found in a single patient with a severe form of infantile onset encephalopathy. We provide new molecular, clinical, and neuroimaging data allowing us to characterize more accurately the molecular spectrum of LYRM7 mutations highlighting that a distinct and recognizable magnetic resonance imaging pattern is related to mutations in this gene. Inter- and intrafamilial variability exists and we observed one patient who was asymptomatic by the age of 6 years.
Assuntos
Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/genética , Imageamento por Ressonância Magnética , Proteínas Mitocondriais/genética , Chaperonas Moleculares/genética , Mutação/genética , Adolescente , Sequência de Aminoácidos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Dados de Sequência Molecular , Saccharomyces cerevisiaeRESUMO
Primary Familial Brain Calcification (PFBC) is a dominantly inherited cerebral microvascular calcifying disorder with diverse neuropsychiatric expression. Three causative genes have been identified: SLC20A2, PDGFRB and, recently, PDGFB, whose associated phenotype has not yet been extensively studied. We included in the largest published case series of genetically confirmed PFBC, 19 PDGFB (including three new mutations), 24 SLC20A2 (including 4 new mutations), and 14 PDGFRB mutation carriers, from two countries (France and Brazil). We studied clinical features and applied our visual rating scale on all 49 available CT scans. Among the symptomatic mutation carriers (33/57, 58%), the three most frequently observed categories of clinical features were psychiatric signs (72.7%, 76.5%, and 80% for PDGFB, SLC20A2, and PDGFRB, respectively), movement disorders (45.5%, 76.5%, and 40%), and cognitive impairment (54.6%, 64.7%, and 40%). The median age of clinical onset was 31 years, 25% had an early onset (before 18) and 25% a later onset (after 53). Patients with an early clinical onset exhibited mostly isolated psychiatric or cognitive signs, while patients with a later onset exhibited mostly movement disorders, especially in association with other clinical features. CT scans rating allowed identifying four patterns of calcification. The total calcification score was best predicted by the combined effects of gene (SLC20A2 > PDGFB > PDGFRB mutations), sex (male), and (increasing) age, defining three risk classes, which correlated with the four patterns of calcification. These calcification patterns could reflect the natural history of the calcifying process, with distinct risk classes characterized by different age at onset or rate of progression.
Assuntos
Encefalopatias Metabólicas Congênitas/genética , Calcinose/genética , Proteínas Proto-Oncogênicas c-sis/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Adulto , Encefalopatias Metabólicas Congênitas/metabolismo , Encefalopatias Metabólicas Congênitas/patologia , Calcificação Fisiológica/genética , Calcinose/metabolismo , Calcinose/patologia , Feminino , Estudos de Associação Genética , Humanos , Masculino , Proteínas Proto-Oncogênicas c-sis/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fatores Sexuais , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismoRESUMO
Primary familial brain calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC.
Assuntos
Encefalopatias Metabólicas Congênitas/genética , Calcinose/genética , Receptores Acoplados a Proteínas G/genética , Receptores Virais/genética , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Células HEK293 , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Doenças Neurodegenerativas/genética , Linhagem , Receptor do Retrovírus Politrópico e XenotrópicoRESUMO
Primary familial brain calcification (PFBC) is a heterogeneous neuropsychiatric disorder, with affected individuals presenting a wide variety of motor and cognitive impairments, such as migraine, parkinsonism, psychosis, dementia, and mood swings. Calcifications are usually symmetrical, bilateral, and found predominantly in the basal ganglia, thalamus, and cerebellum. So far, variants in three genes have been linked to PFBC: SLC20A2, PDGFRB, and PDGFB. Variants in SLC20A2 are responsible for most cases identified so far and, therefore, the present review is a comprehensive worldwide summary of all reported variants to date. SLC20A2 encodes an inorganic phosphate transporter, PiT-2, widely expressed in various tissues, including brain, and is part of a major family of solute carrier membrane transporters. Fifty variants reported in 55 unrelated patients so far have been identified in families of diverse ethnicities and only few are recurrent. Various types of variants were detected (missense, nonsense, frameshift) including full or partial SLC20A2 deletions. The recently reported SLC20A2 knockout mouse will enhance our understanding of disease mechanism and allow for screening of therapeutic compounds. In the present review, we also discuss the implications of these recent exciting findings and consider the possibility of treatments based on manipulation of inorganic phosphate homeostasis.
Assuntos
Encefalopatias/genética , Encefalopatias/patologia , Calcinose/genética , Mutação , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Alelos , Substituição de Aminoácidos , Encefalopatias/diagnóstico , Análise Mutacional de DNA , Éxons , Estudos de Associação Genética , Variação Genética , Humanos , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismoRESUMO
AIMS: Primary familial brain calcification (PFBC) is a rare disorder characterized by abnormal deposits of calcium in the basal ganglia and cerebellum. PFBC can present with a spectrum of neuropsychiatric symptoms resembling those seen in dementia and schizophrenia. Mutations in a few genes have been identified as causing PFBC: namely, the SLC20A2 gene that codes for the sodium-dependent phosphate transporter and the PDGFRB gene that codes for the platelet-derived growth factor receptor ß (PDGF-Rß). A recent study identified mutations in PDGFB coding for PDGF-B, the main ligand for PDGF-Rß, in six families with PFBC. Here we report the first Japanese family with PFBC carrying a mutation in PDGFB, which causes the substitution of an arginine with a stop codon at amino acid 149 of the PDGF-B protein (p. Arg149*). METHODS: Clinical histories and computed tomography scan images were provided. Sanger sequencing was performed for the exome analysis of SLC20A2 and PDGFB genes. RESULTS: One family member began to complain of auditory hallucination at 16 years of age and had been treated for schizophrenia. His father suffered from memory and gait disturbances in his late 60s. A computed tomography scan revealed a symmetrical area of calcification over the basal ganglia in both cases. A known mutation in PDGFB (c.445C>T, p.Arg149*) was consistently detected in both PFBC cases by Sanger sequencing. No mutations in SLC20A2 were detected. CONCLUSIONS: Our findings suggest that this mutation in PDGF-B is responsible for PFBC in this Japanese family and that abnormal PDGF signaling may be involved in the pathophysiology of certain psychiatric disorders.