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

Neurofibromatosis type 2 (NF2) is a monogenic dominantly inherited disease predisposing carriers to develop nervous system tumours. To identify the genetic defect, the region between two flanking polymorphic markers on chromosome 22 was cloned and several genes identified. One is the site of germ-line mutations in NF2 patients and of somatic mutations in NF2-related tumours. Its deduced product has homology with proteins at the plasma membrane and cytoskeleton interface, a previously unknown site of action of tumour suppressor genes in humans.

Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2

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

https://www.cell.com/cell/pdf/0092-8674(87)90158-9.pdf

A genetic linkage map of the human genome

Mendelian Inheritance in Man

https://deepblue.lib.umich.edu/bitstream/handle/2027.42/26679/0000223.pdf;sequence=3

Genetic linkage of von Recklinghausen neurofibromatosis to the nerve growth factor receptor gene

Peripheral neurofibromatosis (NF) is one of the most common major genetic disorders in man. Its chromosomal location is unknown and questions regarding such factors as genetic heterogeneity remain unanswered. We have ascertained and sampled several large multi-generation families for linkage studies including one family of 66 subjects, 28 of whom were affected with NF. Recombinant DNA studies of several restriction fragment length polymorphisms (RFLPs) including C3, ApoC2, pBam34 (D19S6], HAUP[APRT], pE40-1 [D11521], Hp[Hp2 alpha], LDR92, and LDR111 failed to show a significant linkage (Z [lod score] greater than or equal to 3.00) in this family. In addition, the results excluded areas of the genome around the marker loci (Z greater than or equal to - 2.00) as potential sites for linkage. The maximum Z obtained with the markers was for Hp at theta (maximum recombination fraction) = 0.20 and Z = 0.399. We are now in the process of screening additional RFLPs and families for linkage to NF.

https://jmg.bmj.com/content/jmedgenet/24/9/530.full.pdf

G. O D Rossenwasser

Papers

Genetic linkage of von Recklinghausen neurofibromatosis to the nerve growth factor receptor gene

Linkage studies in peripheral neurofibromatosis.