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1.
Eur J Paediatr Neurol ; 27: 25-29, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32553920

RESUMO

Among 1339 unrelated cases accrued by the Italian National Registry for facioscapulohumeral muscular dystrophy (FSHD), we found three unrelated cases who presented signs of Williams-Beuren Syndrome (WBS) in early childhood and later developed FSHD. All three cases carry the molecular defects associated with the two disorders. The rarity of WBS and FSHD, 1 in 7500 and 1 in 20,000 respectively, makes a random association of the two diseases unlikely. These cases open novel and unexpected interpretation of genetic findings. The nonrandom association of both FSHD and WBS points at a gene co-expression network providing hints for the identification of modules and functionally enriched pathways in the two conditions.


Assuntos
Cromossomos Humanos Par 4/genética , Distrofia Muscular Facioescapuloumeral/genética , Síndrome de Williams/genética , Adolescente , Alelos , Criança , Pré-Escolar , Transtornos Cromossômicos/genética , Deleção de Genes , Humanos , Lactente , Itália , Masculino
2.
Ital J Pediatr ; 45(1): 72, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196119

RESUMO

BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare inherited multisystemic disorder with autosomal recessive or complex digenic triallelic inheritance. There is currently no treatment for BBS, but some morbidities can be managed. Accurate molecular diagnosis is often crucial for the definition of appropriate patient management and for the development of a potential personalized therapy. METHODS: We developed a next-generation-sequencing (NGS) protocol for the screening of the 18 most frequently mutated genes to define the genotype and clarify the mutation spectrum of a cohort of 20 BBS Italian patients. RESULTS: We defined the causative variants in 60% of patients; four of those are novel. 33% of patients also harboured variants in additional gene/s, suggesting possible oligogenic inheritance. To explore the function of different genes, we looked for correlations between genotype and phenotype in our cohort. Hypogonadism was more frequently detected in patients with variants in BBSome proteins, while renal abnormalities in patients with variations in BBSome chaperonin genes. CONCLUSIONS: NGS is a powerful tool that can help understanding BBS patients' phenotype through the identification of mutations that could explain differences in phenotype severity and could provide insights for the development of targeted therapy. Furthermore, our results support the existence of additional BBS loci yet to be identified.


Assuntos
Síndrome de Bardet-Biedl/genética , Mutação/genética , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Testes Genéticos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fenótipo
3.
Parkinsonism Relat Disord ; 63: 191-194, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30862453

RESUMO

INTRODUCTION: Spinocerebellar Ataxia 38 (SCA38) is caused by ELOVL5 gene mutation, with significant reduction of serum docosahexaenoic acid (DHA) levels. DHA supplementation has been proven effective at short-term follow-up. In the present paper, we evaluated long-term safety and efficacy of 600 mg/day oral DHA in SCA38 by a 2-year open label extension study. METHODS: Nine SCA38 patients underwent standardised clinical assessment at 62 (T1), 82 (T2) and 104 (T3) weeks, and compared to pre-treatment scores (T0). Brain 18-Fluorodeoxyglucose Positron Emission Tomography and electroneurography were performed at T0 and T3. RESULTS: We found a significant maintenance of clinical symptom improvement at each follow-up time-point (p < 0.001) as compared to T0, a sustained increase of cerebellar metabolism at T3 as compared to T0 (p = 0.013), and no worsening of neurophysiological parameters. No side effect was recorded. CONCLUSIONS: Long-term DHA supplementation is an eligible treatment for SCA38.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/fisiopatologia , Adulto , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/efeitos adversos , Estimulação Elétrica , Eletromiografia , Elongases de Ácidos Graxos/genética , Feminino , Fluordesoxiglucose F18 , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética
4.
Ann Neurol ; 82(4): 615-621, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28976605

RESUMO

OBJECTIVE: Spinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients. METHODS: We enrolled 10 SCA38 patients, and carried out a double-blind randomized placebo-controlled study for 16 weeks, followed by an open-label study with overall 40-week DHA treatment. At baseline and at follow-up visit, patients underwent standardized clinical assessment, brain 18-fluorodeoxyglucose positron emission tomography, electroneurography, and ELOVL5 expression analysis. RESULTS: After 16 weeks, we showed a significant pre-post clinical improvement in the DHA group versus placebo, using the Scale for the Assessment and Rating of Ataxia (SARA; mean difference [MD] = +2.70, 95% confidence interval [CI] = +0.13 to + 5.27, p = 0.042). At 40-week treatment, clinical improvement was found significant by both SARA (MD = +2.2, 95% CI = +0.93 to + 3.46, p = 0.008) and International Cooperative Ataxia Rating Scale (MD = +3.8, 95% CI = +1.39 to + 6.41, p = 0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, false discovery rate corrected). We also showed a decreased expression of ELOVL5 in patients' blood at 40 weeks as compared to baseline. No side effect was recorded. INTERPRETATION: DHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. Ann Neurol 2017;82:615-621.


Assuntos
Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ataxias Espinocerebelares/tratamento farmacológico , Adulto , Ataxinas/genética , Encéfalo/diagnóstico por imagem , Método Duplo-Cego , Eletromiografia , Feminino , Fluordesoxiglucose F18/farmacocinética , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Avaliação de Resultados em Cuidados de Saúde , Tomografia por Emissão de Pósitrons , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Resultado do Tratamento
5.
Parkinsonism Relat Disord ; 28: 80-6, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27143115

RESUMO

INTRODUCTION: SCA38 (MIM 611805) caused by mutations within the ELOVL5 gene, which encodes an enzyme involved in the synthesis of long-chain fatty acids with a high and specific expression in Purkinje cells, has recently been identified. OBJECTIVE: The present study was aimed at describing the clinical and neuroimaging features, and the natural history of SCA38. METHODS: We extended our clinical and brain neuroimaging data on SCA38 including 21 cases from three Italian families. All had the ELOVL5 c.689G > T (p.Gly230Val) missense mutation. RESULTS: Age at disease onset was in the fourth decade of life. The presenting features were nystagmus (100% of cases) and slowly progressive gait ataxia (95%). Frequent signs and symptoms included pes cavus (82%) and hyposmia (76%); rarer symptoms were hearing loss (33%) and anxiety disorder (33%). The disease progressed with cerebellar symptoms such as limb ataxia, dysarthria, dysphagia, and ophtalmoparesis followed in the later stages by ophtalmoplegia. Peripheral nervous system involvement was present in the last phase of disease with sensory loss. Dementia or extrapyramidal signs were not detected. Significant loss of abilities of daily living was reported only after 20 years of the disease. Brain imaging documented cerebellar atrophy with sparing of cerebral cortex and no white matter disease. CONCLUSIONS: SCA38 is a rare form of inherited ataxia with characteristic clinical features, including pes cavus and hyposmia, that may guide genetic screening and prompt diagnosis in light of possible future therapeutic interventions.


Assuntos
Cerebelo/patologia , Progressão da Doença , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/fisiopatologia , Acetiltransferases , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Córtex Cerebelar/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Elongases de Ácidos Graxos , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Linhagem , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética
6.
Clin Chim Acta ; 455: 172-80, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26874042

RESUMO

Jeune asphyxiating thoracic dystrophy (JATD; Jeune syndrome, MIM 208500) is a rare autosomal recessive chondrodysplasia, phenotypically overlapping with short-rib polydactyly syndromes (SRPS). JATD typical hallmarks include skeletal abnormalities such as narrow chest, shortened ribs, limbs shortened bones, extra fingers and toes (polydactyly), as well as extraskeletal manifestations (renal, liver and retinal disease). To date, disease-causing mutations have been found in several genes, highlighting a marked genetic heterogeneity that prevents a molecular diagnosis of the disease in most families. Here, we report the results of whole-exome sequencing (WES) carried out in four JATD cases, belonging to three unrelated families of Sardinian origin. The exome analysis allowed to identify mutations not previously reported in the DYNC2H1 (MIM 603297) and WDR60 (MIM 615462) genes, both codifying for ciliary intraflagellar transport components whose mutations are known to cause Jeune syndrome.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Dineínas do Citoplasma/genética , Síndrome de Ellis-Van Creveld/genética , Mutação , Feminino , Humanos , Itália , Masculino , Linhagem
7.
Eur J Paediatr Neurol ; 20(2): 323-330, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26643067

RESUMO

BACKGROUND: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) was first described in 2002. After the recent identification of TUBB4A mutation as the genetic basis of the disease, the clinical and neuroimaging phenotype related to TUBB4A mutations expanded, ranging from primary dystonia type 4 with normal MRI to severe H-ABC cases. PATIENTS AND METHODS: The study included patients referred to us for an unclassified hypomyelinating leukodystrophy. We selected patients with deleterious heterozygous TUBB4A mutations. Molecular analysis of TUBB4A was performed on genomic DNA extracted from peripheral blood. RESULTS: The series included 12 patients (5 females and 7 males). Five patients carried the common mutation c.745G > A (p.Asp249Asn), while the remaining harbored different mutations. Three new mutations were found in 5 patients. Clinical and neuroimaging observations are described. A clear correlation between the clinical presentation and the genotype seems to be absent in our group of 12 patients. CONCLUSIONS: TUBB4A-mutated patients manifest a comparable clinical and neuroimaging picture but they can differ from each other in terms of rate of disease progression. Extrapyramidal signs can be absent in the first stages of the disease, and a careful evaluation of MRI is fundamental to obtain the final diagnosis. From a therapeutic perspective a trial with l-dopa should be considered in all patients presenting extrapyramidal symptoms.


Assuntos
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Tubulina (Proteína)/genética , Adulto , Progressão da Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Neuroimagem , Fenótipo
8.
Arch Ital Biol ; 153(2-3): 157-61, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26742669

RESUMO

PURPOSE: Jeune syndrome (JS, also described as asphyxiating thoracic dystrophy, ATD) is a rare autosomal recessive skeletal dysplasia characterized by a small, narrow chest and variable limb shortness with a considerable neonatal mortality as a result of respiratory distress. Significant life-threatening cervical spine abnormalities can be typical. METHOD: Here we describe the case of a male infant of Sardinian origin, who developed respiratory distress and feeding difficulties from the first months, correlated with muscle\skeletal dysmorphism prevalent on chest. Nocturnal respiratory sleep alterations were reported from parents. RESULTS: After clinical, genetics, radiographic and cervical MRI investigations, ATD diagnosis with C1 stenosis. A full-night video-polysomnographic study was performed in order to evaluate the sleep apnea condition. The study showed a condition of tachipnea\tachicardia, with several short respiratory events during sleep, both obstructive and central type with apneahypopnea index (AHI) 17/ h, mean duration 3.7 sec with longest 20 sec. CONCLUSION: It can be hypothesized that the combination of altered respiratory and cardiac frequency is related to central type of sleep respiratory disorders consequent to C1 compression, while the obstructive minor component is related to thoracic restrictive disorders. Full night lab-polygraphy is recommended in dysmorphic skeletal disorders like JS.


Assuntos
Síndrome de Ellis-Van Creveld/diagnóstico , Síndromes da Apneia do Sono/diagnóstico , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Polissonografia
9.
Am J Hum Genet ; 95(2): 209-17, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-25065913

RESUMO

Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases.


Assuntos
Acetiltransferases/genética , Metabolismo dos Lipídeos/genética , Mutação/genética , Ataxias Espinocerebelares/genética , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Animais , Ácido Araquidônico/sangue , Cerebelo/patologia , Ácidos Docosa-Hexaenoicos/sangue , Retículo Endoplasmático/metabolismo , Elongases de Ácidos Graxos , Feminino , Ligação Genética , Genótipo , Complexo de Golgi/metabolismo , Haplótipos , Humanos , Itália , Masculino , Camundongos , Pessoa de Meia-Idade , Linhagem , Células de Purkinje/citologia
10.
Hum Mutat ; 35(7): 841-50, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24633898

RESUMO

Kabuki syndrome (KS) is a multiple congenital anomalies syndrome characterized by characteristic facial features and varying degrees of mental retardation, caused by mutations in KMT2D/MLL2 and KDM6A/UTX genes. In this study, we performed a mutational screening on 303 Kabuki patients by direct sequencing, MLPA, and quantitative PCR identifying 133 KMT2D, 62 never described before, and four KDM6A mutations, three of them are novel. We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. Furthermore, we demonstrated that the reduction of KMT2D protein level in patients' lymphoblastoid and skin fibroblast cell lines carrying KMT2D-truncating mutations affects the expression levels of known KMT2D target genes. Finally, we hypothesized that the KS patients may benefit from a readthrough therapy to restore physiological levels of KMT2D and KDM6A proteins. To assess this, we performed a proof-of-principle study on 14 KMT2D and two KDM6A nonsense mutations using specific compounds that mediate translational readthrough and thereby stimulate the re-expression of full-length functional proteins. Our experimental data showed that both KMT2D and KDM6A nonsense mutations displayed high levels of readthrough in response to gentamicin treatment, paving the way to further studies aimed at eventually treating some Kabuki patients with readthrough inducers.


Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Doenças Hematológicas/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/tratamento farmacológico , Linhagem Celular , Códon sem Sentido/efeitos dos fármacos , Estudos de Coortes , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Estudos de Associação Genética , Gentamicinas/farmacologia , Gentamicinas/uso terapêutico , Haploinsuficiência , Doenças Hematológicas/tratamento farmacológico , Histona Desmetilases/genética , Proteínas de Homeodomínio/genética , Humanos , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Degradação do RNAm Mediada por Códon sem Sentido , Proteínas Nucleares/genética , Sítios de Splice de RNA , Análise de Sequência de DNA , Transcrição Gênica , Doenças Vestibulares/tratamento farmacológico
11.
Eur J Med Genet ; 56(4): 207-10, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23419639

RESUMO

Allan-Herndon-Dudley syndrome (AHDS), an X linked condition, is characterized by severe intellectual disability, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia in combination with altered TH levels, in particular, high serum T3 levels. Mutations in the MCT8 gene coding for the monocarboxylate thyroid hormone transporter 8 have been associated with AHDS. Here we describe a family with the presence of a MCT8 gene mutation, p.A224T, in three consecutive generations. In two generations its presence was detected in the hemizygous state in two males with neurological abnormalities including mental retardation, axial hypotonia, hypertonia of arms and legs and athetoid movements. One of them presented normal thyroid hormone levels. Mutation was also detected, although in the heterozygous state, in three females showing thyroid hormone levels in the normal range. Our results show the difficulty of distinguishing AHDS from patients with X-linked intellectual disability solely on the basis of clinical features and biochemical tests, and we advise screening for MCT8 mutations in either young or older patients with severe intellectual disability, axial hypotonia/dystonia, poor head control, spastic paraplegia, and athetoid movements even when they have normal thyroid hormone profiles.


Assuntos
Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/genética , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Atrofia Muscular/diagnóstico , Atrofia Muscular/genética , Mutação de Sentido Incorreto , Fenótipo , Tri-Iodotironina/sangue , Adulto , Criança , Feminino , Heterozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Simportadores
12.
Gene ; 511(2): 437-40, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23026216

RESUMO

We describe a 3-year-old boy who, at age of 8 months, during investigations for upper respiratory tract infection was found to have an incidental grossly elevated CK of 20,000 UI/l. Investigations showed only mild calf hypertrophy and absent Gower's sign, normal cognitive function. Electromyography (EMG) showed myopathic features. Electrocardiography and echocardiography were normal. His muscle biopsy revealed myopathic features indicating Duchenne-type dystrophy. Immunohistochemistry for dystrophin N-terminal, C-terminal and mid-rod antibodies analysis showed the complete absence of dystrophin in the muscle fibers. Genetic studies showed a 141.1 Kb deletion removing muscle promoter, muscle exon 1, Purkinje promoter, Purkinje exon 1, dystrophin muscle enhancers similar to one previously reported in a DMD patient who exhibited some residual expression of dystrophin. The difference in dystrophin expression between these two patients might be due to the extension of deletions. The precise delimitation of the macrodeletion here described provides a better understanding of functional organization of the 5' end of the DMD gene.


Assuntos
Distrofina/genética , Elementos Facilitadores Genéticos , Deleção de Genes , Músculo Esquelético/metabolismo , Regiões Promotoras Genéticas , Biópsia , Pré-Escolar , Eletromiografia , Humanos , Imuno-Histoquímica , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia
13.
Am J Hum Genet ; 90(1): 161-9, 2012 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-22243968

RESUMO

Myhre syndrome is a developmental disorder characterized by reduced growth, generalized muscular hypertrophy, facial dysmorphism, deafness, cognitive deficits, joint stiffness, and skeletal anomalies. Here, by performing exome sequencing of a single affected individual and coupling the results to a hypothesis-driven filtering strategy, we establish that heterozygous mutations in SMAD4, which encodes for a transducer mediating transforming growth factor ß and bone morphogenetic protein signaling branches, underlie this rare Mendelian trait. Two recurrent de novo SMAD4 mutations were identified in eight unrelated subjects. Both mutations were missense changes altering Ile500 within the evolutionary conserved MAD homology 2 domain, a well known mutational hot spot in malignancies. Structural analyses suggest that the substituted residues are likely to perturb the binding properties of the mutant protein to signaling partners. Although SMAD4 has been established as a tumor suppressor gene somatically mutated in pancreatic, gastrointestinal, and skin cancers, and germline loss-of-function lesions and deletions of this gene have been documented to cause disorders that predispose individuals to gastrointestinal cancer and vascular dysplasias, the present report identifies a previously unrecognized class of mutations in the gene with profound impact on development and growth.


Assuntos
Criptorquidismo/genética , Transtornos do Crescimento/genética , Deformidades Congênitas da Mão/genética , Hipertrofia/genética , Deficiência Intelectual/genética , Artropatias/genética , Mutação de Sentido Incorreto , Proteína Smad4/genética , Adolescente , Adulto , Sequência de Bases , Pré-Escolar , Exoma/genética , Fácies , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Transdução de Sinais/genética
14.
Eur J Med Genet ; 53(6): 392-5, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20713192

RESUMO

Thyroid hormones are known to be essential for growth, development and metabolism. Recently mutations in the SLC16A2 gene coding for the monocarboxylate thyroid hormone transporter 8, MCT8, have been associated with Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia. Here we describe in detail the clinical and biochemical features in a boy affected by AHDS with severe neurological abnormalities and a novel de novo SLC16A2 gene insertion, 1343-1344insGCCC, resulting in a truncated protein lacking the last four transmembrane domains (TMDs) as well as the carboxyl cytoplasmic end. He presents mental retardation, axial hypotonia, hypertonia of arms and legs, paroxysmal dyskinesias, seizures. The endocrine phenotype showed low serum total and free thyroxine (T4), very elevated total and free triiodothyronine (T3) and normal thyrotropin (TSH) with blunted response to thyrotropin-releasing hormone (TRH). The latter finding was unexpected and suggested that the lack of functional MCT8 was counterbalanced at the thyrotrope cell level by high serum T3 concentration and/or by increased intrapituitary type 2 deiodinase (D2) activity. Our case constitutes a relevant contribution to better characterize this disorder and to elucidate the functional consequences of SLC16A2 gene mutations.


Assuntos
Mutação da Fase de Leitura/genética , Transportadores de Ácidos Monocarboxílicos/genética , Tireotropina/sangue , Anormalidades Múltiplas/genética , Coreia/genética , Humanos , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/genética , Hipotonia Muscular/genética , Atrofia Muscular/genética , Fenótipo , Simportadores , Tireotropina/genética , Tiroxina/sangue , Tiroxina/genética , Tri-Iodotironina/sangue , Tri-Iodotironina/genética
15.
J Neurol Sci ; 276(1-2): 31-7, 2009 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18976783

RESUMO

The CACNA1A gene codes for the alpha(1A) pore-forming subunit of Ca(2+) voltage-gated Cav2.1 channels. CACNA1A mutations are responsible for Familial Hemiplegic Migraine (FHM) type 1, Episodic Ataxia (EA) type 2 and Spinocerebellar Ataxia type 6. The structure of the human gene includes, at present, 49 exons; however almost nothing is known about the 5' regulatory region, and there is now evidence suggesting the presence of additional exons at the 3' of the gene. The 892 bp fragment upstream of exon 1 and its deletion mutants were characterised for their transcriptional activity by using luciferase as a reporter gene. The 3' region was analysed by Rapid Amplification of the cDNA 3' End. Both regions were screened for mutations in a series of FHM and EA patients by SSCP and sequencing. At the 5' end of the gene a minimal promoter region was identified within the first 497 bp from ATG. By screening a larger fragment for mutations, the 5 bp deletion (g.-757_-753delCTTTC) was identified in a FHM patient. The deletion significantly increased the transcriptional activity, most likely due to the removal of half a turn of the DNA helix, changing the orientation of downstream binding sites for transcriptional factors. At the 3' end of the gene a new exon 48, followed by a strong poly-A signal, was identified as well as a new splice variant. The 5 bp insertion (g.38429_38430insCTTTT) in this exon was found in an EA patient. The two new regions can open the way for the study of human CACNA1A gene expression regulation and can be sites of mutations associated with FHM or EA phenotypes.


Assuntos
Ataxia/genética , Canais de Cálcio/genética , Éxons/genética , Enxaqueca com Aura/genética , Deleção de Sequência/genética , Análise de Variância , Ataxia/sangue , Linhagem Celular Tumoral , Biologia Computacional/métodos , Análise Mutacional de DNA , Humanos , Itália , Enxaqueca com Aura/sangue , Dados de Sequência Molecular , Neuroblastoma/metabolismo , Fenótipo
16.
Am J Hum Genet ; 82(6): 1368-74, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18513679

RESUMO

Deficiency of carbohydrate sulfotransferase 3 (CHST3; also known as chondroitin-6-sulfotransferase) has been reported in a single kindred so far and in association with a phenotype of severe chondrodysplasia with progressive spinal involvement. We report eight CHST3 mutations in six unrelated individuals who presented at birth with congenital joint dislocations. These patients had been given a diagnosis of either Larsen syndrome (three individuals) or humero-spinal dysostosis (three individuals), and their clinical features included congenital dislocation of the knees, elbow joint dysplasia with subluxation and limited extension, hip dysplasia or dislocation, clubfoot, short stature, and kyphoscoliosis developing in late childhood. Analysis of chondroitin sulfate proteoglycans in dermal fibroblasts showed markedly decreased 6-O-sulfation but enhanced 4-O-sulfation, confirming functional impairment of CHST3 and distinguishing them from diastrophic dysplasia sulphate transporter (DTDST)-deficient cells. These observations provide a molecular basis for recessive Larsen syndrome and indicate that recessive Larsen syndrome, humero-spinal dysostosis, and spondyloepiphyseal dysplasia Omani type form a phenotypic spectrum.


Assuntos
Doenças do Desenvolvimento Ósseo/enzimologia , Doenças do Desenvolvimento Ósseo/genética , Disostoses/enzimologia , Disostoses/genética , Luxações Articulares/congênito , Luxações Articulares/genética , Mutação , Sulfotransferases/deficiência , Sulfotransferases/genética , Adolescente , Adulto , Criança , Pré-Escolar , Proteoglicanas de Sulfatos de Condroitina/química , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Feminino , Genes Recessivos , Humanos , Úmero/anormalidades , Recém-Nascido , Luxações Articulares/enzimologia , Masculino , Osteocondrodisplasias/enzimologia , Osteocondrodisplasias/genética , Fenótipo , Coluna Vertebral/anormalidades , Síndrome , Carboidrato Sulfotransferases
17.
Eur J Hum Genet ; 16(6): 696-704, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18270536

RESUMO

Recent studies estimated a rate of 3-5% of cytogenetic abnormalities involving many different chromosomes in autistic spectrum disorders (ASDs). Here, we report on two unrelated male patients with de novo translocations, autistic behaviour and psychomotor delay. These two patients carry a balanced chromosome translocation t(5;8)(q14.3;q23.3) and t(6;8)(q13;q23.2), respectively. A detailed physical map covering the regions involved in the translocations was constructed using BAC clones mapping on chromosomes 5q14.3, 6q13 and 8q23. Fluorescence in situ hybridisation (FISH) analyses were carried out using these genomic clones. We fine mapped the two translocation breakpoints on chromosomes 8 identifying their position within a short 5 Mb genomic region. Breakpoints on chromosomes 8 in both patients do not interrupt any known gene but both map in a region containing the CSMD3 gene, which thereby can be considered as a candidate for ASDs.


Assuntos
Transtorno Autístico/genética , Cromossomos Humanos Par 8 , Proteínas de Membrana/genética , Translocação Genética , Sequência de Bases , Pré-Escolar , Sítios Frágeis do Cromossomo , Cromossomos Humanos Par 5 , Cromossomos Humanos Par 6 , Primers do DNA , Humanos , Hibridização in Situ Fluorescente , Masculino
20.
Nat Genet ; 38(6): 623-5, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16682970

RESUMO

Joubert syndrome-related disorders (JSRD) are a group of syndromes sharing the neuroradiological features of cerebellar vermis hypoplasia and a peculiar brainstem malformation known as the 'molar tooth sign'. We identified mutations in the CEP290 gene in five families with variable neurological, retinal and renal manifestations. CEP290 expression was detected mostly in proliferating cerebellar granule neuron populations and showed centrosome and ciliary localization, linking JSRDs to other human ciliopathies.


Assuntos
Antígenos de Neoplasias/genética , Encéfalo/anormalidades , Mutação , Proteínas de Neoplasias/genética , Animais , Antígenos de Neoplasias/metabolismo , Proteínas de Ciclo Celular , Centrossomo/metabolismo , Proteínas do Citoesqueleto , Humanos , Camundongos , Proteínas de Neoplasias/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Síndrome
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