Von Recklinghausen neurofibromatosis (NF1) is a common autosomal dominant disorder characterized by abnormalities in multiple tissues derived from the neural crest. No reliable cellular phenotypic marker has been identified, which has hampered direct efforts to identify the gene. The chromosome location of the NF1 gene has been previously mapped genetically to 17q11.2, and data from two NF1 patients with balanced translocations in this region have further narrowed the candidate interval. The use of chromosome jumping and yeast artificial chromosome technology has now led to the identification of a large (approximately 13 kilobases) ubiquitously expressed transcript (denoted NF1LT) from this region that is definitely interrupted by one and most likely by both translocations. Previously identified candidate genes, which failed to show abnormalities in NF1 patients, are apparently located within introns of NF1LT, on the antisense strand. A new mutation patient with NF1 has been identified with a de novo 0.5-kilobase insertion in the NF1LT gene. These observations, together with the high spontaneous mutation rate of NF1 (which is consistent with a large locus), suggest that NF1LT represents the elusive NF1 gene.

https://science.sciencemag.org/content/sci/249/4965/181.full.pdf

Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients

https://www.cell.com/cell/pdf/0092-8674(90)90024-9.pdf

The neurofibromatosis type 1 gene encodes a protein related to GAP

https://www.cell.com/cell/pdf/0092-8674(90)90253-B.pdf

A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations.

Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus.

Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.

https://www.embopress.org/doi/pdf/10.15252/embj.201490784

Autophagy in malignant transformation and cancer progression

The gene for von Recklinghausen neurofibromatosis (NF1), one of the most common autosomal-dominant disorders of humans, was recently mapped to chromosome 17 by linkage analysis. The identification of two NF1 patients with balanced translocations that involved chromosome 17q11.2 suggests that the disease can arise by gross rearrangement of the NF1 locus, and that the NF1 gene might be identified by cloning the region around these translocation breakpoints. To further define the region of these translocations, a series of chromosome 17 Not I-linking clones has been mapped to proximal 17q and studied by pulsed-field gel electrophoresis. One clone, 17L1 (D17S133), clearly identifies the breakpoint in an NF1 patient with a t(1;17) translocation. A 2.3-megabase pulsed-field map of this region was constructed and indicates that the NF1 breakpoint is only 10 to 240 kilobases away from 17L1. This finding prepares the way for the cloning of NF1.

https://science.sciencemag.org/content/sci/244/4908/1085.full.pdf

Physical Mapping of a Translocation Breakpoint in Neurofibromatosis

Idiopathic dilated cardiomyopathy is generally considered a sporadic, nongenetic disorder, and reports of familial cases are often regarded as rare occurrences. Results of the present investigation of 6 families with this disorder suggest that familial forms of dilated cardiomyopathy occur more frequently than previously suspected. The familial nature of the dilated cardiomyopathy was not readily apparent in 3 of these families until thorough family investigations had been performed. The clinical symptoms and age of onset were variable from one family to another and within families. Based on these observations, it is recommended that all persons diagnosed with dilated cardiomyopathy have a thorough review of their family history. If there are any cases of unexplained heart disease, sudden unexpected death or syncopal episodes, further investigations of relatives should be performed. Echocardiography is a convenient noninvasive tool for investigating relatives. Early diagnosis of affected relatives is important for 2 reasons--treatment of significant arrhythmias may prevent sudden unexpected death, and genetic counseling can be provided.

Familial dilated cardiomyopathy.

We report on a family in which a mother and her 2 children each had von Recklinghausen neurofibromatosis and a balanced chromosome rearrangement t(1;17)(p34.3;qll.2). In addition, we describe another unrelated patient with neurofibromatosis and a presumed secondary myelodysplastic syndrome in which the bone marrow contained an abnormal clone with an unbalanced rearrangement involving a breakpoint in band 17qll.2. These findings may suggest that the neurofibromatosis gene is located in or near band 17qll.2. This information supports the studies which assign the neurofibromatosis gene to a region of chromosome 17 between the proximal p arm and band q22 on the long arm.

Michael A. Schmidt

Papers

Physical Mapping of a Translocation Breakpoint in Neurofibromatosis

Familial dilated cardiomyopathy.

Cases of neurofibromatosis with rearrangements of chromosome 17 involving band 17q11.2

Characterization of a translocation within the von Recklinghausen neurofibromatosis region of chromosome 17

Spectrum of findings in a family with nonsyndromic autosomal dominant supravalvular aortic stenosis: a Doppler echocardiographic study.