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1.
Eur J Hum Genet ; 26(2): 287-292, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29255276

RESUMO

CHARGE syndrome is a rare genetic disorder mainly due to de novo and private truncating mutations of CHD7 gene. Here we report an intriguing hot spot of intronic mutations (c.5405-7G > A, c.5405-13G > A, c.5405-17G > A and c.5405-18C > A) located in CHD7 IVS25. Combining computational in silico analysis, experimental branch-point determination and in vitro minigene assays, our study explains this mutation hot spot by a particular genomic context, including the weakness of the IVS25 natural acceptor-site and an unconventional lariat sequence localized outside the common 40 bp upstream the acceptor splice site. For each of the mutations reported here, bioinformatic tools indicated a newly created 3' splice site, of which the existence was confirmed using pSpliceExpress, an easy-to-use and reliable splicing reporter tool. Our study emphasizes the idea that combining these two complementary approaches could increase the efficiency of routine molecular diagnosis.

2.
J Med Case Rep ; 11(1): 158, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28615033

RESUMO

BACKGROUND: Xeroderma pigmentosum is an autosomal recessive inherited disease. The diagnosis is essentially based on clinical findings and the family history. This genodermatosis is genetically heterogeneous; to date, nine genes have been associated to this disorder. Based on the result of many studies, xeroderma pigmentosum complementation group C is the most common form of xeroderma pigmentosum. A founder mutation in the XPC gene was reported in the Maghreb region of northern Africa. According to these findings, the Department of Medical Genetics in Rabat offers molecular diagnosis by screening for the recurrent mutation c.1643_1644delTG which represents 74% of all the probands with xeroderma pigmentosum. CASE PRESENTATION: We describe the case of a 21-year-old Moroccan son of consanguineous parents diagnosed with xeroderma pigmentosum on the basis of sun-exposed skin abnormalities and bilateral ocular involvement. A molecular study led to the identification of a new frameshift insertion of four nucleotides in exon 9. CONCLUSIONS: To the best of our knowledge, this mutation has not been described. The sequencing of the ninth exon should be proposed as first line molecular analysis for all Moroccan patients with xeroderma pigmentosum.


Assuntos
Grupo com Ancestrais do Continente Africano , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Mutação da Fase de Leitura/genética , Predisposição Genética para Doença/genética , Xeroderma Pigmentoso/genética , Efeito Fundador , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Marrocos , Prevalência , Xeroderma Pigmentoso/epidemiologia , Adulto Jovem
3.
BMC Res Notes ; 10(1): 188, 2017 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-28577564

RESUMO

BACKGROUND: To date, a limited number of BRCA1/2 germline mutations have been reported in hereditary breast and/or ovarian cancer in the Moroccan population. Less than 20 different mutations of these two genes have been identified in Moroccan patients, and recently we reported a further BRCA2 mutation (c.1310_1313delAAGA; p.Lys437IlefsX22) in three unrelated patients, all from the North-East of the country. We aimed in this study to evaluate the frequency and geographic distribution of this BRCA2 frameshift mutation, in order to access its use as the first-line BRCA genetic testing strategy for Moroccan patients. We enrolled in this study 122 patients from different regions of Morocco, with suggestive inherited predisposition to breast and ovarian cancers. All subjects gave written informed consent to BRCA1/2 genetic testing. According to available resources of our lab and enrolled families, 51 patients were analyzed by the conventional individual exon-by-exon Sanger sequencing, 23 patients were able to benefit from a BRCA next generation sequencing and a target screening for exon 10 of BRCA2 gene was performed in 48 patients. RESULTS: Overall, and among the 122 patients analyzed for at least the exon 10 of the BRCA2 gene, the c.1310_1313delAAGA frameshift mutation was found in 14 patients. Genealogic investigation revealed that all carriers of this mutation shared the same geographic origin and were descendants of the North-East of Morocco. DISCUSSION: In this study, we highlighted that c.1310_1313delAAGA mutation of BRCA2 gene is recurrent with high frequency in patients from the North-East region of Morocco. Therefore, we propose to use, in public health strategies, the detection of this mutation as the first-line screening tests in patients with breast and ovarian cancer originated from this region.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Mutação da Fase de Leitura , Predisposição Genética para Doença/genética , Neoplasias Ovarianas/genética , Proteína BRCA1/genética , Neoplasias da Mama/prevenção & controle , Éxons/genética , Feminino , Frequência do Gene , Testes Genéticos , Geografia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Programas de Rastreamento , Marrocos , Neoplasias Ovarianas/prevenção & controle
4.
Eur J Med Genet ; 60(5): 239-244, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28246031

RESUMO

Jalili syndrome is a rare autosomal recessive genetic disease characterized by the association of amelogenesis imperfecta and cone-rod retinal dystrophy. This syndrome is caused by mutations in the CNNM4 gene. Different types of CNNM4 mutations have been reported; missense, nonsense, large deletions, single base insertion, and duplication. We used Sanger sequencing to analyze a large consanguineous family with three siblings affected with Jalili syndrome, suspected clinically after dental and ophthalmological examination. These patients are carrying a novel homozygous mutation in the splice site acceptor of intron 3 (c.1682-1G > C) in the CNNM4 gene. We compare the findings of the present family to those from literature, in order to further delineate Jalili syndrome.


Assuntos
Amelogênese Imperfeita/genética , Proteínas de Transporte de Cátions/genética , Mutação , Processamento de RNA , Retinite Pigmentosa/genética , Adolescente , Adulto , Distrofias de Cones e Bastonetes , Consanguinidade , Feminino , Humanos , Masculino , Linhagem , Adulto Jovem
5.
Cells ; 5(3)2016 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-27409638

RESUMO

Progeroid laminopathies, including Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #176670), are premature and accelerated aging diseases caused by defects in nuclear A-type Lamins. Most HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type Lamins. This mutation activates a cryptic splice site leading to the deletion of 50 amino acids at its carboxy-terminal domain, resulting in a truncated and permanently farnesylated Prelamin A called Prelamin A Δ50 or Progerin. Some patients carry other LMNA mutations affecting exon 11 splicing and are named "HGPS-like" patients. They also produce Progerin and/or other truncated Prelamin A isoforms (Δ35 and Δ90) at the transcriptional and/or protein level. The results we present show that morpholino antisense oligonucleotides (AON) prevent pathogenic LMNA splicing, markedly reducing the accumulation of Progerin and/or other truncated Prelamin A isoforms (Prelamin A Δ35, Prelamin A Δ90) in HGPS-like patients' cells. Finally, a patient affected with Mandibuloacral Dysplasia type B (MAD-B, carrying a homozygous mutation in ZMPSTE24, encoding an enzyme involved in Prelamin A maturation, leading to accumulation of wild type farnesylated Prelamin A), was also included in this study. These results provide preclinical proof of principle for the use of a personalized antisense approach in HGPS-like and MAD-B patients, who may therefore be eligible for inclusion in a therapeutic trial based on this approach, together with classical HGPS patients.

6.
Mol Syndromol ; 6(1): 44-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25852447

RESUMO

Waardenburg syndrome (WS) is a neurocristopathy disorder combining sensorineural deafness and pigmentary abnormalities. The presence of additional signs defines the 4 subtypes. WS type IV, also called Shah-Waardenburg syndrome (SWS), is characterized by the association with congenital aganglionic megacolon (Hirschsprung disease). To date, 3 causative genes have been related to this congenital disorder. Mutations in the EDNRB and EDN3 genes are responsible for the autosomal recessive form of SWS, whereas SOX10 mutations are inherited in an autosomal dominant manner. We report here the case of a 3-month-old Morrocan girl with WS type IV, born to consanguineous parents. The patient had 3 cousins who died in infancy with the same symptoms. Molecular analysis by Sanger sequencing revealed the presence of a novel homozygous missense mutation c.1133A>G (p.Asn378Ser) in the EDNRB gene. The proband's parents as well as the parents of the deceased cousins are heterozygous carriers of this likely pathogenic mutation. This molecular diagnosis allows us to provide genetic counseling to the family and eventually propose prenatal diagnosis to prevent recurrence of the disease in subsequent pregnancies.

7.
Am J Med Genet A ; 158A(11): 2881-7, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22991222

RESUMO

Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder, characterized by several clinical features that begin in early childhood, recalling an accelerated aging process. The diagnosis of HGPS is based on the recognition of common clinical features and detection of the recurrent heterozygous c.1824C>T (p.Gly608Gly) mutation within exon 11 in the Lamin A/C encoding gene (LMNA). Besides "typical HGPS," several "atypical progeria" syndromes (APS) have been described, in a clinical spectrum ranging from mandibuloacral dysplasia to atypical Werner syndrome. These patients's clinical features include progeroid manifestations, such as short stature, prominent nose, premature graying of hair, partial alopecia, skin atrophy, lipodystrophy, skeletal anomalies, such as mandibular hypoplasia and acroosteolyses, and in some cases severe atherosclerosis with metabolic complications. APS are due in several cases to de novo heterozygous LMNA mutations other than the p.Gly608Gly, or due to homozygous BAFN1 mutations in Nestor-Guillermo Progeria syndrome (NGPS). We report here and discuss the observation of a non-consanguineous Moroccan patient presenting with atypical progeria. The molecular studies showed the heterozygous mutation c.412G>A (p.Glu138Lys) of the LMNA gene. This mutation, previously reported as a de novo mutation, was inherited from the apparently healthy father who showed a somatic cell mosaicism.


Assuntos
Lamina Tipo A/genética , Mutação , Progéria/genética , Sequência de Bases , Criança , Éxons , Evolução Fatal , Feminino , Heterozigoto , Humanos , Fenótipo , Progéria/diagnóstico
8.
J Dermatol ; 39(4): 382-4, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22211393

RESUMO

Xeroderma pigmentosum (XP) is an autosomal recessive inherited disease which is genetically heterogeneous. The prevalence of this genodermatosis is estimated to be 1/1 000 000 in the USA; it is more common in Japan and probably in other populations with high levels of consanguinity. The molecular diagnosis and identification of mutation in patients requires the knowledge of the causative gene by the determination of XP complementation groups. Soufir et al. have reported that XPC is the major disease-causing gene with a recurrent mutation in the Mediterranean region. The mutation c.1643_1644delTG (p.Val548AlafsX25) represents alone 74% of all the XP probands tested and 87% in XP type C in North African patients with founder effect. We used molecular epidemiological methods in the present study to calculate the frequency of heterozygote for this mutation in Moroccan newborns and estimate the prevalence of XP in the Moroccan population. DNA extracted from umbilical cord blood samples of 250 newborns were tested for the recurrent XPC mutation c.1643_1644delTG using real-time polymerase chain reaction. Heterozygotes profiles were confirmed by direct sequencing. Among 250 newborns tested, one subject was heterozygous for the mutation c.1643_1644delTG. The carrier frequency was estimated to be 1/250 which would imply that the prevalence of XP would be approximately 1/80 504 considering the effect of consanguinity. This is the first report of the prevalence of XP in an Arab country and it shows that the prevalence of xeroderma pigmentosum is higher than that found in Europe and the USA.


Assuntos
Proteínas de Ligação a DNA/genética , Xeroderma Pigmentoso/epidemiologia , Xeroderma Pigmentoso/genética , Feminino , Efeito Fundador , Frequência do Gene , Heterozigoto , Humanos , Recém-Nascido , Masculino , Marrocos/epidemiologia , Prevalência , Reação em Cadeia da Polimerase em Tempo Real , Deleção de Sequência
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