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1.
Am J Hum Genet ; 102(1): 69-87, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29290338

RESUMO

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.


Assuntos
Códon/genética , Estudos de Associação Genética , Mutação de Sentido Incorreto/genética , Neurofibromatose 1/genética , Neurofibromina 1/genética , Adolescente , Sequência de Aminoácidos , Criança , Estudos de Coortes , Simulação por Computador , Demografia , Feminino , Heterozigoto , Humanos , Masculino , Neurofibromina 1/química , Fenótipo , Adulto Jovem
2.
Hum Mutat ; 41(1): 299-315, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31595648

RESUMO

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.


Assuntos
Alelos , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Neurofibromina 1/genética , Substituição de Aminoácidos , Estudos Transversais , Heterozigoto , Humanos , Fenótipo
4.
Genet Med ; 21(4): 867-876, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30190611

RESUMO

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.


Assuntos
Deficiências da Aprendizagem/genética , Neurofibroma Plexiforme/genética , Neurofibromatose 1/genética , Neurofibromina 1/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Humanos , Lactente , Deficiências da Aprendizagem/fisiopatologia , Masculino , Mutação de Sentido Incorreto/genética , Neurofibroma Plexiforme/fisiopatologia , Neurofibromatose 1/patologia , Deleção de Sequência , Adulto Jovem
5.
Hum Mutat ; 36(11): 1052-63, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26178382

RESUMO

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.


Assuntos
Substituição de Aminoácidos , Códon , Mutação de Sentido Incorreto , Neurofibromina 1/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Nanismo/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neurofibromina 1/química , Adulto Jovem
6.
Ecol Appl ; 21(4): 1024-30, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21774409

RESUMO

Prions, which cause chronic wasting disease and other transmissible spongiform encephalopathies in ungulates, can remain active in soils for years. The reproductive age of ungulate populations is well within the residence time of prions in the soil. Reproduction and mortality in disease-free wildlife populations is regulated by density-dependent mechanisms, which also underlie the concept of carrying capacity. Here, we present a model of a susceptible deer population with density-dependent population regulation, an infected population, and an environmental pool of prions that infect the susceptible animals. When carrying capacity is low, the disease does not persist. As carrying capacity increases beyond a critical level, chronic wasting disease then invades a susceptible population and persists. Further increases in carrying capacity beyond a second, higher critical level produce stable limit cycles and recurrent epidemics between the animal population and the disease. This model therefore extends Rosenzweig's paradox of enrichment for predator-prey models to models of diseases in populations. The critical carrying capacities are reached sooner as the residence time of the prion in the soil increases. Wildlife management programs which increase carrying capacity may cause chronic wasting disease to persist and even destabilize animal populations, especially where prions persist for many years.


Assuntos
Cervos/metabolismo , Modelos Biológicos , Doença de Emaciação Crônica/transmissão , Animais , Ecossistema , Príons , Doença de Emaciação Crônica/metabolismo
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