Novel recurrent nonsense mutation causing neurofibromatosis type 1 (NF1) in a family segregating both NF1 and Noonan syndrome

Abstract

Neurofibromatosis type 1 (NF1), a genetic disorder with neuroectodermal involvement, demonstrates phenotypic overlap in some patients with Noonan syndrome (NS), ultimately resulting in the so-called neurofibromatosis-Noonan syndrome (NF-NS). A strong association of the two phenotypic traits was recently illustrated by a four-generation family, although NF1 and NS were eventually demonstrated to segregate independently on the basis of polymorphic DNA markers [Bahuau et al., 1996: Am J Med Genet 66:347-355]. Identification of the causal NF1 mutation seemed a prerequisite to further dissecting this singular familial association. Using the protein truncation assay, a nonsense mutation (C2446T-->R816X) of the neurofibromin gene was evidenced. This mutation occurred on a CpG dinucleotide within exon 16 and 5' to the GAP domain-specifying region of the gene. R816X creates a recognition site for endonuclease HphI, absent in 2 individuals with NS only. Screening 184 unrelated NF1 patients, three novel occurrences of the mutation were found in individuals diagnosed with classical NF1. Based on the assumption of genotype-phenotype correlation in these individuals, clinical and molecular analyses of this four-generation family demonstrated that the NF-NS phenotype was additive, being the result of both classical NF1 and NS. This particular observation also suggests the presence of an NS locus on 17q, which might be of interest for further linkage studies.

Clinically aggressive central giant cell granulomas in two patients with neurofibromatosis 1

“…Noonan syndrome, an entity of its own right, is believed to be the result of the independent segregation of a both classical NF1 phenotype and a Noonan syndrome phenotype. 42 The observation that the genes responsible for these 2 conditions are located on separate chromosomes does not rule out the possibility of an as yet undefined interaction between neurofibromin and the Noonan syndrome gene product SHP-2. However, the basis for this apparent association between these 2 conditions and CGCGs of the jaws remains unclear.…”

Clinically aggressive central giant cell granulomas in two patients with neurofibromatosis 1

“…NF1-Noonan syndrome, an entity of its own right, is believed to be the result of the independent segregation of a both classical NF1 phenotype and a Noonan syndrome phenotype. 42 The observation that the genes responsible for these 2 conditions are located on separate chromosomes does not rule out the possibility of an as yet undefined interaction between neurofibromin and the Noonan syndrome gene product SHP-2. However, the basis for this apparent association between these 2 conditions and CGCGs of the jaws remains unclear.…”

NF1 Gene Mutations are the Major Molecular Event in Neurofibromatosis-Noonan Syndrome

“…The gene of neurofibromatosis type 1 is located at chromosome 17q11.2 [2]. Approximately 50% of all affected individuals carry de novo mutations [3,4].…”

“…Approximately 50% of all affected individuals carry de novo mutations [3,4]. Typical appearances are café-au lait spots, peripheral neurofibromas, Lisch nodules, axillary and inguinal freckling,, malignant peripheral nerve sheath tumors (MPNST) (Neurofibromas as a benign form and Neurofibrosarcomas as a malignant forms) and other malignancies such as intracranial astrocytomas, gastrointestinal stromal tumors, pheochromocytomas, and juvenile monocytic leukemia [2,5]. Endocrine symptoms, neurological and ophthalmological problems are the other manifestations that appear less frequently [6].…”

“…The clinical feature of NS is short stature, congenital heart defects, unusual pectus deformity, and typical facial features, such as hypertelorism, ptosis, downslanting palpebral fissures, low-set posteriorly rotated ears, and a broad forehead. Additional associated features include neonatal failure to thrive, bleeding abnormalities, mild intellectual disability, multiple skeletal defects, and various skin manifestations, for example, cafe´-au-lait spots [2,8,9] with both hematopoietic malignancies and malignant solid Tumors [10]. Nine genes involved in the RAS-MAPK pathway are known to be associated with 70-85% of patients with NS or NS-like conditions.…”