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1.
Mol Biol Rep ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31583567

RESUMO

De novo mutations in the IRF2BPL gene have been identified to date in 18 patients presenting with neuromotor regression, epilepsy and variable neurological signs. Here, we report a female child carrying a novel heterozygous truncating variant in IRF2BPL. Following normal development for two and half years, she developed a progressive neurological condition with psychomotor regression, dystonic tetraparesis with hyperkinetic movements, but no overt epilepsy. Skin biopsy revealed enlarged lysosomes containing granular and tubular material, suggestive of a lysosomal storage disorder. This case expands the IRF2BPL phenotypic spectrum, for the first time providing evidence of endolysosomal storage.

2.
Brain ; 142(10): 2965-2978, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31412107

RESUMO

Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30403813

RESUMO

Background: Joubert syndrome (JS) is an inherited ciliopathy characterized by a complex midbrain-hindbrain malformation and multiorgan involvement. Renal disease, mainly juvenile nephronophthisis (NPH), was reported in 25-30% patients although only ∼18% had a confirmed diagnosis of chronic kidney disease (CKD). NPH often remains asymptomatic for many years, resulting in delayed diagnosis. The aim of the study was to identify a biomarker able to quantify the risk of progressive CKD in young children with JS. Methods: Renal features were investigated in 93 Italian patients, including biochemical tests, ultrasound and 1-deamino-8D-arginine vasopressin test in children with reduced basal urine osmolality. A subset of patients was followed-up over time. Results: At last examination, 27 of 93 subjects (29%) presented with CKD, ranging from isolated urinary concentration defect (UCD) to end-stage renal disease. Both normal and pathological urine osmolality levels remained stable over time, even when obtained at very early ages. Follow-up data showed that the probability of developing CKD can be modelled as a function of the urine osmolality value, exceeding 75% for levels <600 mOsm/kg H2O, and significantly increased in patients with an early diagnosis of isolated UCD. Conclusions: We conclude that the frequency of CKD in JS increases with age and is higher than previously reported. Urine osmolality represents an early sensitive quantitative biomarker of the risk of CKD progression.

5.
Eur J Med Genet ; 61(10): 585-595, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29605658

RESUMO

Mutations in CPLANE1 (previously known as C5orf42) cause Oral-Facial-Digital Syndrome type VI (OFD6) as well as milder Joubert syndrome (JS) phenotypes. Seven new cases from five unrelated families diagnosed with pure OFD6 were systematically examined. Based on the clinical manifestations of these patients and those described in the literature, we revised the diagnostic features of OFD6 and include the seven most common characteristics: 1) molar tooth sign, 2) tongue hamartoma and/or lobulated tongue, 3) additional frenula, 4) mesoaxial polydactyly of hands, 5) preaxial polydactyly of feet, 6) syndactyly and/or bifid toe, and 7) hypothalamic hamartoma. By whole or targeted exome sequencing, we identified seven novel germline recessive mutations in CPLANE1, including missense, nonsense, frameshift and canonical splice site variants, all causing OFD6 in these patients. Since CPLANE1 is also mutated in JS patients, we examined whether a genotype-phenotype correlation could be established. We gathered and compared 46 biallelic CPLANE1 mutations reported in 32 JS and 26 OFD6 patients. Since no clear correlation between paired genotypes and clinical outcomes could be determined, we concluded that patient's genetic background and gene modifiers may modify the penetrance and expressivity of CPLANE1 causal alleles. To conclude, our study provides a comprehensive view of the phenotypic range, the genetic basis and genotype-phenotype association in OFD6 and JS. The updated phenotype scoring system together with the identification of new CPLANE1 mutations will help clinicians and geneticists reach a more accurate diagnosis for JS-related disorders.

6.
Am J Hum Genet ; 101(4): 552-563, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28965847

RESUMO

The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild "molar tooth sign"), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Cerebelo/anormalidades , Anormalidades Craniofaciais/genética , Anormalidades do Olho/genética , Genes Recessivos , Proteínas Hedgehog/metabolismo , Doenças Renais Císticas/genética , Mutação de Sentido Incorreto , Proteínas Repressoras/genética , Retina/anormalidades , Anormalidades Múltiplas/patologia , Doenças do Desenvolvimento Ósseo/patologia , Células Cultivadas , Cerebelo/patologia , Criança , Estudos de Coortes , Anormalidades Craniofaciais/patologia , Anormalidades do Olho/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Doenças Renais Císticas/patologia , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Retina/patologia , Análise de Sequência de DNA , Transdução de Sinais , Pele/metabolismo , Pele/patologia , Proteína Gli3 com Dedos de Zinco
8.
Biochim Biophys Acta Mol Basis Dis ; 1863(12): 3303-3312, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28807751

RESUMO

The neuron-restricted isoform 3 of the plasma membrane Ca2+ ATPase plays a major role in the regulation of Ca2+ homeostasis in the brain, where the precise control of Ca2+ signaling is a necessity. Several function-affecting genetic mutations in the PMCA3 pump associated to X-linked congenital cerebellar ataxias have indeed been described. Interestingly, the presence of co-occurring mutations in additional genes suggest their synergistic action in generating the neurological phenotype as digenic modulators of the role of PMCA3 in the pathologies. Here we report a novel PMCA3 mutation (G733R substitution) in the catalytic P-domain of the pump in a patient affected by non-progressive ataxia, muscular hypotonia, dysmetria and nystagmus. Biochemical studies of the pump have revealed impaired ability to control cellular Ca2+ handling both under basal and under stimulated conditions. A combined analysis by homology modeling and molecular dynamics have revealed a role for the mutated residue in maintaining the correct 3D configuration of the local structure of the pump. Mutation analysis in the patient has revealed two additional function-impairing compound heterozygous missense mutations (R123Q and G214S substitution) in phosphomannomutase 2 (PMM2), a protein that catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate. These mutations are known to be associated with Type Ia congenital disorder of glycosylation (PMM2-CDG), the most common group of disorders of N-glycosylation. The findings highlight the association of PMCA3 mutations to cerebellar ataxia and strengthen the possibility that PMCAs act as digenic modulators in Ca2+-linked pathologies.

9.
Eur Radiol ; 27(12): 5080-5092, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28677066

RESUMO

OBJECTIVE: To determine the neuroimaging pattern of cerebellar dysplasia (CD) and other posterior fossa morphological anomalies associated with mutations in tubulin genes and to perform clinical and genetic correlations. METHODS: Twenty-eight patients harbouring 23 heterozygous pathogenic variants (ten novel) in tubulin genes TUBA1A (n = 10), TUBB2B (n = 8) or TUBB3 (n = 5) were studied by a brain MRI scan performed either on a 1.5 T (n = 10) or 3 T (n = 18) MR scanner with focus on the posterior fossa. RESULTS: Cerebellar anomalies were detected in 24/28 patients (86%). CD was recognised in 19/28 (68%) including cortical cerebellar dysplasia (CCD) in 18/28, either involving only the cerebellar hemispheres (12/28) or associated with vermis dysplasia (6/28). CCD was located only in the right hemisphere in 13/18 (72%), including four TUBB2B-, four TUBB3- and five TUBA1A-mutated patients, while in the other five TUBA1A cases it was located only in the left hemisphere or in both hemispheres. The postero-superior region of the cerebellar hemispheres was most frequently affected. CONCLUSIONS: The cerebellar involvement in tubulinopathies shows specific features that may be labelled as 'tubulin-related CD'. This pattern is unique and differs from other genetic causes of cerebellar dysplasia. KEY POINTS: • Cortical cerebellar dysplasia without cysts is suggestive of tubulin-related disorder. • Cerebellar dysplasia in tubulinopathies shows specific features labelled as 'tubulin-related CD'. • Focal and unilateral involvement of cerebellar hemispheres has important implications for counselling.


Assuntos
Cerebelo/anormalidades , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Neuroimagem/métodos , Tubulina (Proteína)/genética , Adulto , Tronco Encefálico/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Adulto Jovem
10.
Neurogenetics ; 17(3): 191-5, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27251579

RESUMO

Dysequilibrium syndrome (DES) is a non-progressive congenital ataxia characterized by severe intellectual deficit, truncal ataxia and markedly delayed, quadrupedal or absent ambulation. Recessive loss-of-function mutations in the very low density lipoprotein receptor (VLDLR) gene represent the most common cause of DES. Only two families have been reported harbouring homozygous missense mutations, both with a similarly severe phenotype. We report an Italian girl with very mild DES caused by the novel homozygous VLDLR missense mutation p.(C419Y). This unusually benign phenotype possibly relates to a less disruptive effect of the mutation, falling within a domain (EGF-B) not predicted as crucial for the protein function.


Assuntos
Ataxia Cerebelar/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Receptores de LDL/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/patologia , Criança , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Linhagem
11.
J Med Genet ; 53(9): 608-15, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27208211

RESUMO

BACKGROUND: Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene. METHODS: Exome sequencing was performed in 145 patients with Joubert syndrome (JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes. RESULTS: We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy (JATD). The CEP120-associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype. CONCLUSION: Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Mutação/genética , Retina/anormalidades , Sequência de Aminoácidos , Doenças Cerebelares/genética , Criança , Ciliopatias/genética , Encefalocele/genética , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Humanos , Masculino , Taxa de Mutação , Síndromes Orofaciodigitais/genética , Linhagem , Fenótipo , Alinhamento de Sequência
12.
Eur J Hum Genet ; 24(9): 1262-7, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26932191

RESUMO

Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti-Boltshauser syndrome (PBS). Clinical features comprise non-progressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS. Here we report the detailed clinical, neuroimaging and genetic characterization of 18 PBS patients from 15 unrelated families. Biallelic LAMA1 variants were identified in 14 families (93%). The only non-mutated proband presented atypical clinical and neuroimaging features, challenging the diagnosis of PBS. Sixteen distinct variants were identified, which were all novel. In particular, the frameshift variant c.[2935delA] recurred in six unrelated families on a shared haplotype, suggesting a founder effect. No LAMA1 variants could be detected in 27 probands with different cerebellar dysplasias or non-progressive cerebellar ataxia, confirming the strong correlate between LAMA1 variants and PBS.


Assuntos
Ataxia Cerebelar/genética , Cerebelo/anormalidades , Cistos/genética , Oftalmopatias/genética , Deficiência Intelectual/genética , Laminina/genética , Adolescente , Ataxia Cerebelar/diagnóstico , Cerebelo/diagnóstico por imagem , Criança , Pré-Escolar , Cistos/diagnóstico , Oftalmopatias/diagnóstico , Feminino , Efeito Fundador , Mutação da Fase de Leitura , Haplótipos , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Masculino , Linhagem , Síndrome
13.
Brain Imaging Behav ; 10(1): 158-67, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25832852

RESUMO

Aim of this study is to show the potential of probabilistic tractographic techniques, based on the Constrained Spherical Deconvolution (CSD) algorithms, in recognizing white matter fiber bundle anomalies in patients with complex cerebral malformations, such as cerebellar agenesis. The morphological and tractographic study of a 17-year-old male patient affected by cerebellar agenesis was performed by using a 3Tesla MRI scanner. Genetic and neuropsychological tests were carried out. An MRI morphological study showed the absence of both cerebellar hemispheres and the flattening of the anterior side of the pons. Moreover, it showed a severe vermian hypoplasia with a minimal vermian residual. The study recognized two thin cerebellar remnants, medially in contact with the small vermian residual, at the pontine level. The third ventricle, morphologically normal, communicated with a permagna cerebello-medullary cistern. Probabilistic CSD tractography identified some abnormal and aberrant infratentorial tracts, symmetrical on both sides. In particular, the transverse pontine fibers were absent and the following tracts with aberrant trajectories have been identified: "cerebello-thalamic" tracts; "fronto-cerebellar" tracts; and ipsilateral and contralateral "spino-cerebellar" tracts. Abnormal tracts connecting the two thin cerebellar remnants have also been detected. There were no visible alterations in the main supratentorial tracts in either side. Neuropsychiatric evaluation showed moderate cognitive-motor impairment with discrete adaptive compensation. Probabilistic CSD tractography is a promising technique that overcome reconstruction biases of other diffusion tensor-based approaches and allowed us to recognize, in a patient with cerebellar agenesis, abnormal tracts and aberrant trajectories of normally existing tracts.


Assuntos
Algoritmos , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Processamento de Imagem Assistida por Computador/métodos , Adolescente , Humanos , Masculino , Vias Neurais/anormalidades , Vias Neurais/diagnóstico por imagem , Ponte/anormalidades , Ponte/diagnóstico por imagem , Substância Branca/anormalidades , Substância Branca/diagnóstico por imagem
14.
Hum Genet ; 134(1): 123-6, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25407461

RESUMO

Oral-facial-digital type VI syndrome (OFDVI) is a rare phenotype of Joubert syndrome (JS). Recently, C5orf42 was suggested as the major OFDVI gene, being mutated in 9 of 11 families (82 %). We sequenced C5orf42 in 313 JS probands and identified mutations in 28 (8.9 %), most with a phenotype of pure JS. Only 2 out of 17 OFDVI patients (11.7 %) were mutated. A comparison of mutated vs. non-mutated OFDVI patients showed that preaxial and mesoaxial polydactyly, hypothalamic hamartoma and other congenital defects may predict C5orf42 mutations, while tongue hamartomas are more common in negative patients.


Assuntos
Doenças Cerebelares/genética , Anormalidades do Olho/genética , Hamartoma/genética , Doenças Hipotalâmicas/genética , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Mutação/genética , Síndromes Orofaciodigitais/genética , Retina/anormalidades , Anormalidades Múltiplas , Doenças Cerebelares/patologia , Cerebelo/anormalidades , Estudos de Coortes , Anormalidades do Olho/patologia , Família , Feminino , Seguimentos , Hamartoma/patologia , Humanos , Doenças Hipotalâmicas/patologia , Doenças Renais Císticas/patologia , Masculino , Síndromes Orofaciodigitais/patologia , Fenótipo , Retina/patologia
15.
Orphanet J Rare Dis ; 9: 72, 2014 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-24886560

RESUMO

Joubert syndrome is a clinically and genetically heterogeneous ciliopathy characterized by a typical cerebellar and brainstem malformation (the "molar tooth sign"), and variable multiorgan involvement. To date, 24 genes have been found mutated in Joubert syndrome, of which 13 also cause Meckel syndrome, a lethal ciliopathy with kidney, liver and skeletal involvement. Here we describe four patients with mild Joubert phenotypes who carry pathogenic mutations in either MKS1 or B9D1, two genes previously implicated only in Meckel syndrome.


Assuntos
Doenças Cerebelares/genética , Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Mutação , Doenças Renais Policísticas/genética , Proteínas/genética , Retina/anormalidades , Anormalidades Múltiplas , Adulto , Doenças Cerebelares/patologia , Cerebelo/anormalidades , Criança , Pré-Escolar , Transtornos da Motilidade Ciliar/patologia , Encefalocele/patologia , Anormalidades do Olho/patologia , Feminino , Humanos , Doenças Renais Císticas/patologia , Imagem por Ressonância Magnética , Masculino , Doenças Renais Policísticas/patologia , Retina/patologia , Retinite Pigmentosa , Índice de Gravidade de Doença
16.
Hum Mutat ; 35(1): 137-46, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24166846

RESUMO

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


Assuntos
Doenças Cerebelares/genética , Doenças Cerebelares/metabolismo , Cílios/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Retina/anormalidades , Fatores de Ribosilação do ADP/metabolismo , Anormalidades Múltiplas , Animais , Cerebelo/anormalidades , Exoma , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Masculino , Modelos Moleculares , Linhagem , Prenilação de Proteína , Proteômica , Retina/metabolismo , Análise de Sequência de DNA , Peixe-Zebra/anormalidades , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
17.
Lancet Neurol ; 12(9): 894-905, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23870701

RESUMO

Joubert syndrome is a congenital cerebellar ataxia with autosomal recessive or X-linked inheritance, the diagnostic hallmark of which is a unique cerebellar and brainstem malformation recognisable on brain imaging-the so-called molar tooth sign. Neurological signs are present from the neonatal period and include hypotonia progressing to ataxia, global developmental delay, ocular motor apraxia, and breathing dysregulation. These signs are variably associated with multiorgan involvement, mainly of the retina, kidneys, skeleton, and liver. 21 causative genes have been identified so far, all of which encode for proteins of the primary cilium or its apparatus. The primary cilium is a subcellular organelle that has key roles in development and in many cellular functions, making Joubert syndrome part of the expanding family of ciliopathies. Notable clinical and genetic overlap exists between distinct ciliopathies, which can co-occur even within families. Such variability is probably explained by an oligogenic model of inheritance, in which the interplay of mutations, rare variants, and polymorphisms at distinct loci modulate the expressivity of the ciliary phenotype.


Assuntos
Doenças Cerebelares/congênito , Doenças Renais Císticas/congênito , Anormalidades Múltiplas , Doenças Cerebelares/epidemiologia , Doenças Cerebelares/genética , Cerebelo/anormalidades , Anormalidades do Olho/epidemiologia , Anormalidades do Olho/genética , Humanos , Doenças Renais Císticas/epidemiologia , Doenças Renais Císticas/genética , Retina/anormalidades
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