Mental retardation and cardiovascular malformations in NF1 microdeleted patients point to candidate genes in 17q11.2

Venturin, Marco; Guarnieri, Paolo; Natacci, Federica; Stabile, M; Tenconi, Romano; Clementi, Maurizio; Hernandez, C; Thompson, Patrick; Upadhyaya, Meena; Larizza, Lidia; Riva, Paola

doi:10.1136/jmg.2003.014761

Cited by 115 publications

(121 citation statements)

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“…The first correlation relates to patients with NF1 and NF1 microdeletions, which cover the entire NF1 gene and lead to a severe form of NF1. 29,30 Patients with an NF1 microdeletion have a higher burden of cutaneous neurofibromas, may have dysmorphic features, and often develop learning disabilities. The second association involves a specific, 3-bp, in-frame deletion in exon 17 (c.2970-2972 delAAT) of the NF1 gene, a condition that is characterized by a mild phenotype in many patients.…”

Section: Genotype-phenotype Correlations In Nf1mentioning

confidence: 99%

The Pathoetiology of Neurofibromatosis 1

Jouhilahti

Peltonen

Heape

et al. 2011

The American Journal of Pathology

158

150

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Although a mutation in the NF1 gene is the only factor required to initiate the neurocutaneous-skeletal neurofibromatosis 1 (NF1) syndrome, the pathoetiology of the multiple manifestations of this disease in different organ systems seems increasingly complex. The wide spectrum of different clinical phenotypes and their development, severity, and prognosis seem to result from the cross talk between numerous cell types, cell signaling networks, and cell-extracellular matrix interactions. The bi-allelic inactivation of the NF1 gene through a "second hit" seems to be of crucial importance to the development of certain manifestations, such as neurofibromas, café-au-lait macules, and glomus tumors. In each case, the second hit involves only one cell type, which is subsequently clonally expanded in a discrete lesion. Neurofibromas, which are emphasized in this review, and cutaneous neurofibromas in particular, are known to contain a subpopulation of NF1-diploinsufficient Schwann cells and a variety of NF1-haploinsufficient cell types. A recent study identified a multipotent precursor cell population with an NF1 ؉/؊ genotype that resides in human cutaneous neurofibromas and that has been suggested to play a role in their pathogenesis. café-au-lait macules and multiple benign cutaneous neurofibromas, which, typically, are detectable in adulthood by simple visual inspection.NF1 can affect nearly every organ system, and the complications vary between individuals, even within a single family. The clinical diagnosis is based on the presence of two or more of the following findings: six or more café-au-lait macules with diameters Ͼ5 mm in prepubertal patients and Ͼ15 mm in postpubertal patients; two or more neurofibromas of any type or one plexiform neurofibroma; axillary or inguinal freckling; optic glioma; two or more Lisch nodules of the iris; a distinctive osseous lesion, such as sphenoid wing dysplasia or pseudarthrosis; or a first-degree relative diagnosed as having NF1 according to the preceding criteria. 3 It has been suggested that a pathogenic mutation in the NF1 gene be added to the list of diagnostic criteria. 4 The most common complications of NF1 are included in the previously listed diagnostic criteria. Additional features include short stature, scoliosis, headache, speech disorders, attention deficit disorder and attention-deficit/ hyperactivity disorder, and learning disabilities. Rare complications, affecting Ͻ5% of patients, include epilepsy, hydrocephalus, cardiovascular problems, and dystrophic scoliosis. 5 The lifetime risk of malignant tumors arising from peripheral nerves is estimated to be 10% to 13%. 6 The pathoetiology of the complications in NF1 is, however, largely unknown. Genetic BackgroundNF1 is caused by mutations in the NF1 gene that encodes the tumor suppressor protein neurofibromin. 7,8 The NF1 gene is located on chromosome band 17q11.2, spanning approximately 280 kb of genomic DNA, and is composed of 57 constitutive exons and 4 alternatively spliced exons (9a, 10a2, 23a, and 48a). 9 Howeve...

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Section: Genotype-phenotype Correlations In Nf1mentioning

confidence: 99%

The Pathoetiology of Neurofibromatosis 1

Jouhilahti

Peltonen

Heape

et al. 2011

The American Journal of Pathology

158

150

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“…In addition, one can create a series of mutant alleles with a spectrum of severities to study the consequences of varying levels of residual gene function. Extremely clever methods, with origins in yeast genetics, allow the revelation of cell-autonomous neuronal phenotypes, at very high resolu- [Venturin et al 2004].…”

Section: Power and Potential Of The Fly Genetics Toolboxmentioning

confidence: 99%

Mental retardation genes in drosophila: New approaches to understanding and treating developmental brain disorders

Restifo

2005

Ment. Retard. Dev. Disabil. Res. Rev.

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Drosophila melanogaster is emerging as a valuable genetic model system for the study of mental retardation (MR). MR genes are remarkably similar between humans and fruit flies. Cognitive behavioral assays can detect reductions in learning and memory in flies with mutations in MR genes. Neuroanatomical methods, including some at single-neuron resolution, are helping to reveal the cellular bases of faulty brain development caused by MR gene mutations. Drosophila fragile X mental retardation 1 (dfmr1) is the fly counterpart of the human gene whose malfunction causes fragile X syndrome. Research on the fly gene is leading the field in molecular mechanisms of the gene product's biological function and in pharmacological rescue of brain and behavioral phenotypes. Future work holds the promise of using genetic pathway analysis and primary neuronal culture methods in Drosophila as tools for drug discovery for a wide range of MR and related disorders.

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“…12,13 In addition, patients with deletions often have larger regions deleted than just the immediate gene, which can cause features more typical of chromosomal abnormalities, such as mental retardation, birth defects, and behavioral anomalies. 14,15 Because of its utility in diagnosing individuals with nonspecific clinical findings, aCGH may detect DNA copy gains or losses that can predispose to neoplasm (Table 1). We report our experience with diagnosis of cancer syndromes using aCGH and present case examples to demonstrate how this genotype-first approach to diagnostic testing refines and guides medical management and improves clinical outcome.…”

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confidence: 99%