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1.
Brain ; 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29985992

RESUMO

The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes.

2.
J Exp Med ; 215(5): 1327-1336, 2018 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-29636373

RESUMO

Ubiquitously expressed Cbl-interacting protein of 85 kD (CIN85) is a multifunctional adapter molecule supposed to regulate numerous cellular processes that are critical for housekeeping as well as cell type-specific functions. However, limited information exists about the in vivo roles of CIN85, because only conditional mouse mutants with cell type-specific ablation of distinct CIN85 isoforms in brain and B lymphocytes have been generated so far. No information is available about the roles of CIN85 in humans. Here, we report on primary antibody deficiency in patients harboring a germline deletion within the CIN85 gene on the X chromosome. In the absence of CIN85, all immune cell compartments developed normally, but B lymphocytes showed intrinsic defects in distinct effector pathways of the B cell antigen receptor, most notably NF-κB activation and up-regulation of CD86 expression on the cell surface. These results reveal nonredundant functions of CIN85 for humoral immune responses.

3.
Am J Med Genet A ; 176(3): 663-667, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29314551

RESUMO

Sheldon-Hall syndrome (SHS) is the most common of the distal arthrogryposes (DAs), a group of disorders characterized by congenital non-progressive contractures. Patients with SHS present with contractures of the limbs and a distinctive triangular facies with prominent nasolabial folds. Calcaneovalgus deformity is frequent, as well as camptodactyly and ulnar deviation. Causative mutations in at least four different genes have been reported (MYH3, TNNI2, TPM2, and TNNT3). MYH3 plays a pivotal role in fetal muscle development and mutations in this gene are associated with Freeman-Sheldon syndrome, distal arthrogryposis 8 (DA8), and autosomal dominant spondylocarpotarsal synostosis. The last two disorders are characterized by skeletal abnormalities, in particular bony fusions. The observation that MYH3 may be mutated in these syndromes has suggested the involvement of this gene in bone development. We report the case of a boy with a novel pathogenic MYH3 mutation, presenting with the classical clinical features of SHS in association with unilateral carpal bone fusion and multiple vertebral fusions. This distinctive phenotype has never been reported in the literature so far and expands the phenotypic spectrum of SHS, endorsing the clinical variability of patients with MYH3-related disorders. Our findings also support a role for MYH3 in both muscle and bone development, suggesting a phenotypic continuum in MYH3-related disorders.

5.
Am J Med Genet A ; 161A(10): 2634-40, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23949945

RESUMO

An increasing number of patients with 3p proximal deletions were reported in the previous decade, but the region responsible for the main features such as intellectual disability (ID) and developmental delay is not yet characterized. Here we report on two monozygotic twin brothers of 2 10/12 years and an 18-year-old man, all three of them displaying severe ID, psychomotoric delay, autistic features, and only mild facial dysmorphisms. Array CGH (aCGH), revealed a 6.55 Mb de novo interstitial deletion of 3p14.1p14.3 in the twin brothers and a 4.76 Mb interstitial deletion of 3p14.1p14.2 in the 18-year-old patient, respectively. We compared the malformation spectrum with previous molecularly well-defined patients in the literature and in the DECIPHER database (Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources; http://decipher.sanger.ac.uk/). In conclusion, the deletion of a region containing 3p14.2 seems to be associated with a relative concise phenotype including ID and developmental delay. Thus, we hypothesize that 3p14.2 is the potential core region in 3p proximal deletions. The knowledge of this potential core region could be helpful in the genetic counselling of patients with 3p proximal deletions, especially concerning their phenotype.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 3 , Gêmeos Monozigóticos/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Pré-Escolar , Mapeamento Cromossômico , Hibridização Genômica Comparativa , Facies , Humanos , Masculino , Fenótipo
6.
Eur J Med Genet ; 56(8): 458-62, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23811035

RESUMO

Distal deletion 9p is associated with gonadal dysfunction in XY individuals. Little is known about the gonadal function and fertility of XX females with this condition. We report on an affected 31-year-old infertile woman presenting with premature ovarian failure, mild dysmorphic features, a history of mild developmental delay and an otherwise normal female phenotype. Cytogenetic analysis showed a deletion 9p with the karyotype 46,XX,del(9)(p23-24) in lymphocytes. The subsequent oligonucleotide array-based CGH analysis with genomic DNA from peripheral blood revealed a terminal deletion of approximately 7.6 Mb. SNP microarray analyses of the patient and her unaffected parents confirmed the deletion breakpoint and revealed a de novo mutation of paternal origin. This is apparently the first description of an adult woman with a cytogenetically visible terminal deletion of chromosome 9p. The fertility problems observed in this patient complement earlier findings in prepubertal and pubertal 46,XX-girls with 9p deletions, who displayed a phenotype ranging from primary ovarian dysfunction and mild gonadotropin hyperresponses to positive menses. DMRT1 is hemizygous in our patient. We discuss the role of DMRT1 in female gonadal development.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 9 , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/genética , Adulto , Bandeamento Cromossômico , Hibridização Genômica Comparativa , Feminino , Humanos
7.
Neuropediatrics ; 44(5): 268-71, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23436495

RESUMO

Terminal deletions of chromosome 3p26.3 confined to the CHL1 gene have previously been described in children with intellectual disability and epilepsy. Here, we report for the first time, a 3p26.3 duplication including only the CHL1 gene in an intellectually disabled girl with epilepsy. The penetrance of both deletions and duplications in 3p26.3 is reduced because all chromosomal imbalances were inherited from healthy parents. Further studies are needed to specify the pathogenic mechanism of 3p26.3 imbalances and to estimate recurrence risks in genetic counseling. However, the description of both deletions and duplications of chromosome 3p26.3 in nonsyndromic intellectual disability suggests that CHL1 is a dosage-sensitive gene with an important role for normal cognitive development.


Assuntos
Moléculas de Adesão Celular/genética , Cognição/fisiologia , Epilepsia/genética , Deficiência Intelectual/genética , Adolescente , Duplicação Cromossômica , Epilepsia/complicações , Feminino , Humanos , Deficiência Intelectual/complicações , Fenótipo
8.
BMC Urol ; 13: 3, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23320739

RESUMO

BACKGROUND: Papillary renal cell carcinoma is a rare cancer. Some cases can be attributed to individuals with hereditary renal cell carcinomas usually consisting of the clear cell subtype. In addition, two syndromes with hereditary papillary renal cell carcinoma have been described. One is the hereditary leiomyomatosis and renal cell carcinoma, which is characterized by cutaneous and uterine leiomyomas and renal cell carcinoma mostly consisting of the papillary renal cell carcinoma type II with a worse prognosis. CASE PRESENTATION: We describe a case of a 30-year-old woman with hereditary leiomyomatosis and renal cell carcinoma syndrome with extensively metastasized papillary renal cell carcinoma, primarily diagnosed in a cervical lymph node lacking leiomyomas at any site. CONCLUSION: Papillary renal cell carcinoma in young patients should be further investigated for a hereditary variant like the hereditary leiomyomatosis and renal cell carcinoma even if leiomyomas could not be detected. A detailed histological examination and search for mutations is essential for the survival of patients and relatives.


Assuntos
Carcinoma de Células Renais/secundário , Neoplasias Renais/secundário , Linfonodos/patologia , Neoplasias Primárias Múltiplas/genética , Adulto , Biópsia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Feminino , Fumarato Hidratase/genética , Predisposição Genética para Doença , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Leiomiomatose/genética , Leiomiomatose/patologia , Metástase Linfática , Mutação de Sentido Incorreto , Pescoço , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Cutâneas , Neoplasias Uterinas
10.
Eur J Med Genet ; 55(8-9): 480-4, 2012 Aug-Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22677035

RESUMO

We report on monochorionic diamniotic male twins discordant for the trisomy 12p syndrome. Trisomy 12p mosaicism with a supernumerary der(12)(pter > q12) was detected in approximately 50% of lymphocytes in both children. Fluorescence in situ hybridisation (FISH) revealed a high grade mosaicism of approximately 77% trisomy 12p cells in buccal smear and 85% in hair follicles in the affected twin, while in the normal developing brother an additional 12p chromosome fragment could not be detected in those tissues. Instead, in 3% of buccal smear and hair follicle cells a minute supernumerary marker chromosome comprising central portions of chromosome 12 was observed. Trisomy 12p mosaicism, confined to the lymphocytes of the unaffected twin, may be due to prenatal twin-to-twin transfusion, explaining the conspicuously discordant clinical phenotype. We discuss the possible sequence of events leading to the cytogenetic findings and compare the clinical phenotype presented in the affected twin with other cases of trisomy 12p and tetrasomy 12p (Pallister-Killian syndrome).


Assuntos
Anormalidades Múltiplas/diagnóstico , Cromossomos Humanos Par 12/genética , Mosaicismo , Trissomia/diagnóstico , Gêmeos Monozigóticos/genética , Cariótipo Anormal , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Células Cultivadas , Pré-Escolar , Hibridização Genômica Comparativa , Genótipo , Humanos , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Fenótipo , Trissomia/genética , Trissomia/patologia
11.
Am J Med Genet A ; 158A(3): 652-8, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22315187

RESUMO

Noonan syndrome (NS) is a common autosomal dominant condition characterized by short stature, congenital heart defects, and dysmorphic facial features caused in approximately 50% of cases by missense mutations in the PTPN11 gene. NS patients are predisposed to malignancies including myeloproliferative disorders or leukemias. We report a female NS patient carrying a PTPN11 germline mutation c.417 G > C (p.E139D), who developed in her second year of life an acute lymphoblastic leukemia (ALL) and after remission, she developed at 4 years of age a juvenile myelomonocytic leukemia (JMML). Molecular genetic analysis of lymphoblastic blasts at the time of the ALL diagnosis revealed the germline mutation in a heterozygous state, while in the myelomonocytic blasts occurring with JMML diagnosis, the mutation p.E139D was found in a homozygous state due to a uniparental disomy (UPD). These findings lead to the suggestion that the pathogenesis of ALL and JMML in our patient is due to different mechanisms including somatically acquired secondary chromosomal abnormalities.


Assuntos
Mutação em Linhagem Germinativa , Leucemia Mielomonocítica Juvenil/complicações , Síndrome de Noonan/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Hibridização Genômica Comparativa , Feminino , Heterozigoto , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
12.
Am J Med Genet A ; 158A(2): 429-33, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22246919

RESUMO

Interstitial deletions of the distal part of chromosome 2p are rare, with only six reported cases involving regions from 2p23 to 2pter. Most of these were cytogenetic investigations. We describe a 14-year-old boy with an 8.97 Mb deletion of 2p23.3-24.3 detected by array comparative genomic hybridization (array CGH) who had intellectual disability (ID), unusual facial features, cryptorchidism, skeletal myopathy, dilated cardiomyopathy (DCM), and postnatal overgrowth (macrocephaly and tall stature). We compared the clinical features of the present case to previously described patients with an interstitial deletion within this chromosomal region and conclude that our patient exhibits a markedly different phenotype. Additional patients are needed to further delineate phenotype-genotype correlations.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Estudos de Associação Genética , Adolescente , Transtornos Dismórficos Corporais/diagnóstico , Transtornos Dismórficos Corporais/genética , Transtornos Dismórficos Corporais/patologia , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/patologia , Hibridização Genômica Comparativa , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Doenças Musculares/patologia
13.
Metallomics ; 4(2): 197-204, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22089129

RESUMO

Copper is an essential micronutrient for all living organisms. ATP7A protein is a copper-transporting ATPase which plays a vital role in the maintenance of cellular copper homeostasis in mammals. This protein is retained within the trans-Golgi network, but after binding copper it can be translocated to the cell membrane to participate in the efflux of excess Cu. Mutation of the ATP7A gene in humans results in the severe neurodegenerative disorder, Menkes disease. The mouse ATP7A homolog encodes a protein that plays the same role in copper transport. Mosaic mutant mice display a lethal phenotype which resembles Menkes disease, although the underlying molecular defect has not been characterized until now. In the present study we identified a G to C nucleotide exchange in exon 15 of the Atp7a gene in mosaic mutants, which resulted in an arginine to proline substitution in the highly conserved 6th transmembrane domain of the ATP7A protein. This mutated protein was mislocalized in kidney cells isolated from mosaic mutant mice, and following exposure of these cells to increased copper concentrations it was not translocated to the plasma membrane. Disturbance of ATP7A function in mosaic mice results in increased copper accumulation in the small intestine and kidneys, and in Cu deficiency in the brain, liver and heart. Mouse models of Menkes disease belong to the mottled mutant group. The mosaic mutant represents another interesting animal model for Menkes disease that will be of value in research on copper metabolism and transport in mammals.


Assuntos
Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Cobre/metabolismo , Síndrome dos Cabelos Torcidos/genética , Síndrome dos Cabelos Torcidos/metabolismo , Substituição de Aminoácidos , Animais , Transporte Biológico Ativo , Western Blotting , ATPases Transportadoras de Cobre , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Túbulos Renais/citologia , Túbulos Renais/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Mosaicismo , Mutação , Especificidade de Órgãos , Estrutura Terciária de Proteína
14.
Am J Med Genet A ; 158A(1): 229-35, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22140031

RESUMO

Interstitial deletions of the proximal chromosome 16q are rare. To date, only six cases with molecularly well-characterized microdeletions within this chromosomal region have been described. We report on a patient with severe psychomotor delay, dysmorphic features, microcephaly and hypoplasia of the corpus callosum, epilepsy, a heart defect, and pronounced muscular hypotonia. Array comparative genomic hybridization (aCGH) revealed that the patient's features were likely caused by a 4.7 Mb de novo deletion on chromosome 16q12.1q12.2, which was confirmed by quantitative real-time PCR (qPCR). The psychomotor delay and craniofacial dysmorphism are more severe in our patient than previously reported patients. Unmasked recessive mutations in the ZNF423 and FTO genes on the remaining allele were excluded as the putative cause for this severe phenotype. In conclusion, the phenotypic spectrum of microdeletions in 16q12 is broad and comprises variable degrees of psychomotor delay and intellectual disability, craniofacial anomalies, and additional features, including heart defects, brain malformations, and limb anomalies.


Assuntos
Encéfalo/anormalidades , Deleção Cromossômica , Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Cromossomos Humanos Par 16/genética , Hibridização Genômica Comparativa , Extremidades/anatomia & histologia , Humanos , Lactente , Masculino , Microcefalia/genética , Hipotonia Muscular/genética , Fenótipo , Proteínas/genética , Reação em Cadeia da Polimerase em Tempo Real
15.
Am J Med Genet A ; 155A(8): 2003-7, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21739600

RESUMO

Alterations of the Fragile Mental Retardation 2 gene (FMR2, synonym AFF2) can result in non-specific, mild to borderline X-linked intellectual disability (XLID), and behavioral problems. The well-known molecular pathomechanism of this condition, also referred to as FRAXE, is a (CCG)(n) trinucleotide repeat expansion which leads to silencing of the FMR2 gene. However, deletions within the FMR2 gene may also be causative of the disorder. Here, we report on two brothers diagnosed with FRAXE in whom a small deletion in the FMR2 gene was detected by whole genome array comparative genomic hybridization (CGH). The deletion was also present in their clinically healthy mother and maternal uncle who was similarly affected, but not in a healthy older brother of the two patients. Our observation demonstrates that FMR2 gene deletions may contribute to the FRAXE phenotype. Therefore, we suggest that screening for FMR2 gene deletions using array CGH should be considered in patients with non-specific XLID and absent trinucleotide expansion.


Assuntos
Transtorno Autístico/genética , Cromossomos Humanos X/genética , Síndrome do Cromossomo X Frágil/genética , Deleção de Genes , Proteínas Nucleares/genética , Criança , Hibridização Genômica Comparativa , Síndrome do Cromossomo X Frágil/diagnóstico , Estudos de Associação Genética , Humanos , Masculino
16.
Brain Stimul ; 3(4): 230-7, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20965453

RESUMO

BACKGROUND: The brain-derived neurotrophic factor (BDNF) gene is involved in mechanisms of synaptic plasticity in the adult brain. It has been demonstrated that BDNF also plays a significant role in shaping externally induced human brain plasticity. Plasticity induced in the human motor cortex by intermittent theta-burst stimulation (iTBS) was impaired in individuals expressing the Val66Met polymorphism. METHODS: To explore whether this polymorphism is also important for other neuroplasticity-inducing tools in humans with modes of action differing from that of iTBS, namely, transcranial direct current (tDCS) and random noise stimulation (tRNS), we retrospectively analyzed the data of 64 subjects studied in our laboratory with regard to BDNF genotype. RESULTS: Fifteen subjects with the Val66Met allele, 46 subjects with the Val66Val allele, and 3 Met66Met carriers were identified. The response of the Val66Met allele carriers to stimulation differed in two protocols compared with the response of Val66Val individuals. For iTBS (15 subjects, 5 heterozygotes), plasticity could be only induced in the Val66Val allele carriers. However, for facilitatory tDCS (24 subjects, 10 heterozygotes), as well as for inhibitory tDCS, (19 subjects, 8 heterozygotes), carriers of the Val66Met allele displayed enhanced plasticity, whereas for transcranial random noise stimulation (29 subjects, 8 heterozygotes), the difference between groups was not so pronounced. CONCLUSIONS: BDNF polymorphism has a definite impact on plasticity in humans, which might differ according to the mechanism of plasticity induction. This impact of BDNF on plasticity should be taken into account for future studies, as well as having wider ranging implications for the treatment of neuropsychiatric disorders with transcranial stimulation tools, as it may predetermine their efficacy for the treatment of disease and rehabilitation.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Córtex Cerebral/fisiologia , Plasticidade Neuronal/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estimulação Elétrica/métodos , Feminino , Humanos , Masculino , Plasticidade Neuronal/fisiologia , Estudos Retrospectivos , Adulto Jovem
17.
Cancer Res ; 70(11): 4569-79, 2010 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20460541

RESUMO

Cancer stem cell studies may improve understanding of tumor pathophysiology and identify more effective strategies for cancer treatment. In a variety of organisms, Piwil2 has been implicated in multiple roles including stem cell self-renewal, RNA silencing, and translational control. In this study, we documented specific expression of the stem cell protein Piwil2 in breast cancer with predominant expression in breast cancer stem cells. In patients who were evaluated, we determined that 90% of invasive carcinomas and 81% of carcinomas in situ exhibited highest expression of Piwil2. In breast cancer cells, Piwil2 silencing suppressed the expression of signal transducer and activator of transcription 3, a pivotal regulator of Bcl-X(L) and cyclin D1, whose downregulation paralleled a reduction in cell proliferation and survival. Our findings define Piwil2 and its effector signaling pathways as key factors in the proliferation and survival of breast cancer stem cells.


Assuntos
Neoplasias da Mama/patologia , Células-Tronco Neoplásicas/patologia , Proteínas/fisiologia , Apoptose/fisiologia , Proteínas Argonauta , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/fisiologia , Regiões Promotoras Genéticas , Proteínas/genética , Proteínas/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Proteína bcl-X/metabolismo
18.
Hum Mutat ; 31(5): 617-21, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20186691

RESUMO

An autosomal recessive form of hereditary spastic paraplegia (AR-HSP) is primarily caused by mutations in the SPG7 gene, which codes for paraplegin, a subunit of the hetero-oligomeric m-AAA protease in mitochondria. In the current study, sequencing of the SPG7 gene in the genomic DNA of 25 unrelated HSP individuals/families led to the identification of two HSP patients with compound heterozygous mutations (p.G349S/p.W583C and p.A510V/p.N739KfsX741) in the coding sequence of the SPG7 gene. We used a yeast complementation assay to evaluate the functional consequence of novel SPG7 sequence variants detected in the HSP patients. We assessed the proteolytic activity of hetero-oligomeric m-AAA proteases composed of paraplegin variant(s) and proteolytically inactive forms of AFG3L2 (AFG3L2(E575Q) or AFG3L2(K354A)) upon expression in m-AAA protease-deficient yeast cells. We demonstrate that the newly identified paraplegin variants perturb the proteolytic function of hetero-oligomeric m-AAA protease. Moreover, commonly occurring silent polymorphisms such as p.T503A and p.R688Q could be distinguished from mutations (p.G349S, p.W583C, p.A510V, and p.N739KfsX741) in our HSP cohort. The yeast complementation assay thus can serve as a reliable system to distinguish a pathogenic mutation from a silent polymorphism for any novel SPG7 sequence variant, which will facilitate the interpretation of genetic data for SPG7.


Assuntos
Análise Mutacional de DNA/métodos , Metaloendopeptidases/genética , Saccharomyces cerevisiae/metabolismo , Paraplegia Espástica Hereditária/genética , Proteases Dependentes de ATP , ATPases Associadas a Diversas Atividades Celulares , Adenosina Trifosfatases/genética , Humanos , Polimorfismo Genético , Saccharomyces cerevisiae/genética , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/metabolismo
19.
Eur J Hum Genet ; 17(2): 187-94, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18701882

RESUMO

The SPAST gene encoding for spastin plays a central role in the genetically heterogeneous group of diseases termed hereditary spastic paraplegia (HSP). In this study, we attempted to expand and refine the genetic and phenotypic characteristics of SPAST associated HSP by examining a large cohort of HSP patients/families. Screening of 200 unrelated HSP cases for mutations in the SPAST gene led to detection of 57 mutations (28.5%), of which 47 were distinct and 29 were novel mutations. The distribution analysis of known SPAST mutations over the structural domains of spastin led to the identification of several regions where the mutations were clustered. Mainly, the clustering was observed in the AAA (ATPases associated with diverse cellular activities) domain; however, significant clustering was also observed in the MIT (microtubule interacting and trafficking), MTBD (microtubule-binding domain) and an N-terminal region (228-269 residues). Furthermore, we used a previously generated structural model of spastin as a framework to classify the missense mutations in the AAA domain from the HSP patients into different structural/functional groups. Our data also suggest a tentative genotype-phenotype correlation and indicate that the missense mutations could cause an earlier onset of the disease.


Assuntos
Adenosina Trifosfatases/genética , Análise Mutacional de DNA , Paraplegia Espástica Hereditária/genética , Idade de Início , Humanos , Mutação de Sentido Incorreto , Paraplegia Espástica Hereditária/epidemiologia , Paraplegia Espástica Hereditária/fisiopatologia , Espastina
20.
Swiss Med Wkly ; 138(29-30): 432-6, 2008 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-18654869

RESUMO

UNLABELLED: Hereditary haemorrhagic telangiectasia (HHT), associated with arteriovenous malformations, is a genetic disease of the vascular system with a frequency of approx. 1:10,000. Genetic diagnosis serves to identify individuals at risk of developing the disease and is a useful tool for genetic counselling purposes. QUESTIONS UNDER STUDY: Here we report on a child presenting severe arteriovenous malformations leading to heart failure. Her mother and grandmother present fewer symptoms of hereditary haemorrhagic telangiectasia. In this study we identify the cause of HHT in the family. METHODS: Clinical examination, PCR, DNA sequencing, quantitative PCR, Southern blot, xray, ultrasound, cardiac catheterisation and angiocardiography. RESULTS: Initially the sequence variant in c.392C>T in the endoglin gene was detected in the grandmother, but not in other affected family members. Further analyses revealed a deletion of exon 1 of endoglin, segregating with the phenotype. CONCLUSIONS: This report points out the need for careful evaluation of molecular genetic findings, particularly in diseases with highly variable phenotype.


Assuntos
Fenótipo , Telangiectasia Hemorrágica Hereditária/fisiopatologia , Técnicas de Laboratório Clínico , DNA/sangue , DNA/isolamento & purificação , Alemanha , Humanos , Lactente , Índice de Gravidade de Doença , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/etiologia , Telangiectasia Hemorrágica Hereditária/genética
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