Abstract Neurofibromatosis type 1 (NF1), a neuroectodermal disorder, is caused by germline mutations in the NF1 gene. NF1 affects approximately 1/3,000 individuals worldwide, with about 50% of cases representing de novo mutations. Although the NF1 gene was identified in 1990, the underlying gene mutations still remain undetected in a small but obdurate minority of NF1 patients. We postulated that in these patients, hitherto undetected pathogenic mutations might occur in regulatory elements far upstream of the NF1 gene. In an attempt to identify such remotely acting regulatory elements, we reasoned that some of them might reside within DNA sequences that (1) have the potential to interact at distance with the NF1 gene and (2) lie within a histone H3K27ac-enriched region, a characteristic of active enhancers. Combining Hi-C data, obtained by means of the chromosome conformation capture technique, with data on the location and level of histone H3K27ac enrichment upstream of the NF1 gene, we predicted in silico the presence of two remotely acting regulatory regions, located, respectively, approximately 600 kb and approximately 42 kb upstream of the NF1 gene. These regions were then sequenced in 47 NF1 patients in whom no mutations had been found in either the NF1 or SPRED1 gene regions. Five patients were found to harbour DNA sequence variants in the distal H3K27ac-enriched region. Although these variants are of uncertain pathological significance and still remain to be functionally characterized, this approach promises to be of general utility for the detection of mutations underlying other inherited disorders that may be caused by mutations in remotely acting regulatory elements.
Somatic gene mutations constitute key events in the malignant transformation of human cells. Somatic mutation can either actively speed up the growth of tumour cells or relax the growth constraints normally imposed upon them, thereby conferring a selective (proliferative) advantage at the cellular level. Neurofibromatosis type-1 (NF1) affects 1/3,000-4,000 individuals worldwide and is caused by the inactivation of the NF1 tumour suppressor gene, which encodes the protein neurofibromin. Consistent with Knudson's two-hit hypothesis, NF1 patients harbouring a heterozygous germline NF1 mutation develop neurofibromas upon somatic mutation of the second, wild-type, NF1 allele. While the identification of somatic mutations in NF1 patients has always been problematic on account of the extensive cellular heterogeneity manifested by neurofibromas, the classification of NF1 somatic mutations is a prerequisite for understanding the complex molecular mechanisms underlying NF1 tumorigenesis. Here, the known somatic mutational spectrum for the NF1 gene in a range of NF1-associated neoplasms - including peripheral nerve sheath tumours (neurofibromas), malignant peripheral nerve sheath tumours, gastrointestinal stromal tumours, gastric carcinoid, juvenile myelomonocytic leukaemia, glomus tumours, astrocytomas and phaeochromocytomas - have been collated and analysed.
Consensus clinical diagnostic criteria for neurofibromatosis type I (NF1) include café-au-lait macules and skinfold freckling. The former are frequently the earliest manifestation of NF1, and as such are of particular significance when assessing young children at risk of the condition. A phenotype of predominantly spinal neurofibromatosis has been identified in a small minority of families with NF1, often in association with a relative or absolute lack of cutaneous manifestations. An association with splicing and missense mutations has previously been reported for spinal neurofibromatosis, but on the basis of molecular results in only a few families.
Method
Patients with spinal NF1 were identified through the Manchester nationally commissioned service for complex NF1.
Results
Five families with spinal NF1 were identified, with a broad spectrum of NF1 mutations, providing further evidence that this phenotype may arise in association with any genre of mutation in this gene. Pigmentary manifestations were absent or very mild in affected individuals. Several further affected individuals, some with extensive spinal root tumours, were ascertained when additional family members were assessed.
Conclusions
Clinical NF1 consensus criteria cannot be used to exclude the diagnosis of spinal NF1, especially in childhood. This emphasises the importance of molecular confirmation in individuals and families with atypical presentations of NF1.
Over 20 years ago, Watson described three families with a condition characterised by pulmonary valvular stenosis, café au lait patches, and dull intelligence. Short stature is an additional feature of this autosomal dominant condition. A fourth family with Watson syndrome has since been reported. We have had the opportunity to review members of three of these four families. The clinical phenotype of Watson syndrome has been expanded to include relative macrocephaly and Lisch nodules in the majority of affected subjects, and neurofibromas in one-third of family members. Because the additional clinical findings enhance the similarity between Watson syndrome and neurofibromatosis 1, molecular linkage studies have been performed using probes flanking the NF1 gene on chromosome 17. Probe HHH202 showed the tightest linkage to Watson syndrome with a maximum lod score of 3.59 at phi = 0.0 (95% confidence limits of phi = 0.0-0.15). This suggests either that Watson syndrome and neurofibromatosis 1 are allelic, or that there is a series of contiguous genes for pulmonary stenosis, neurocutaneous anomalies, short stature, and mental retardation on 17q.
Journal Article Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generational effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD) Get access Peter W. Lunt, Peter W. Lunt * 1Clinical Genetics Department, Institute of Child Health, Bristol Childrens Hospital, Bristol BS2 8BJ, UK2Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, UK *To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar Philip E. Jardine, Philip E. Jardine 1Clinical Genetics Department, Institute of Child Health, Bristol Childrens Hospital, Bristol BS2 8BJ, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Manuela C. Koch, Manuela C. Koch 3Medizinsches Zentrum fur Humangenetik, Philipps Universitat, Marburg 35033, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Julie Maynard, Julie Maynard 2Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael Osborn, Michael Osborn 2Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Maggie Williams, Maggie Williams 4Department of Clinical Chemistry, Southmead Hospital, Bristol BS10 5NB, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Peter S. Harper, Peter S. Harper 2Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Meena Upadhyaya Meena Upadhyaya 2Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Human Molecular Genetics, Volume 4, Issue 5, May 1995, Pages 951–958, https://doi.org/10.1093/hmg/4.5.951 Published: 01 May 1995 Article history Received: 09 January 1995 Revision received: 03 March 1995 Accepted: 03 March 1995 Published: 01 May 1995
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