Search PubMed⌕ Search

Biomedical subjects

V M Riccardi

Publications and source records attributed to V M Riccardi.

At least 19 recordsLinked to original sources
PubMed1995

Methods for rapid detection of a recurrent nonsense mutation and documentation of phenotypic features in neurofibromatosis type 1 patients.

We have developed a rapid screening method to detect a recurrent mutation in the neurofibromatosis type 1 gene. Using gene amplification and hybridization with allele-specific oligonucleotides, we screened 97 unrelated affected individuals for the recurrent C-->T substitution in codon 1947. The mutation was detected in 1 patient and found to cosegregate with the disease phenotype in the patient's family. Although the estimated prevalence of this mutation is low, rapid screening of different patient cohorts would identify multiple individuals carrying the same mutation. Such data would provide the first opportunity for examining correlations between phenotypic characteristics and molecular genotype and would allow clinicians to offer early diagnosis and prenatal screening to affected families. A format for the comparison of phenotypic features in other settings is presented.

Base Sequence↗
PubMed1995

Ocular abnormalities in neurofibromatosis 2.

PURPOSE: To evaluate the ocular abnormalities in patients with clinically diagnosed neurofibromatosis 2 and asymptomatic gene carriers. METHODS: Probands were ascertained through a surgical otolaryngology practice. In a cross-sectional study, we examined 49 patients with neurofibromatosis 2, 30 offspring of patients, and, as a comparison group, 18 parents and siblings of patients with sporadic neurofibromatosis 2. The examination included a complete neuro-ophthalmic assessment, physical examination, and, for patients and first-degree relatives at risk, cranial and spinal magnetic resonance imaging with gadolinium enhancement, if not previously performed. RESULTS: The most common ocular abnormalities were posterior subcapsular or capsular, cortical, or mixed lens opacities in 33 (67%) of 49 patients with neurofibromatosis 2 and retinal hamartomas in 11 (22%). We used segregation analysis to determine the mutation carrier status of six at-risk offspring who were 30 years old or younger in two multigeneration families. Three asymptomatic mutation carriers had cataracts, whereas those who were predicted not to carry the mutation did not have cataracts. Asymptomatic mutation carriers may have developmental abnormalities of the eye that are detectable in childhood or adolescence, a finding that may assist in early diagnosis of the disease. CONCLUSIONS: A variety of ocular abnormalities are present in neurofibromatosis 2, including cataracts, retinal hamartomas, and ocular motor deficits. Many of these are developmental or acquired early in life and may assist in presymptomatic diagnosis. For screening at-risk relatives of patients with neurofibromatosis 2, the types of cataract that are most suggestive of neurofibromatosis 2 are plaque-like posterior subcapsular or capsular cataract and cortical cataract with onset under the age of 30 years.

Adolescent↗
PubMed1994

Familial multiple cafe au lait spots.

BACKGROUND: Familial multiple cafe au lait spots (CLS) represent a rare, autosomal dominant pigmentary disorder characterized by the multiple CLS seen in neurofibromatosis type 1 (NF-1) but differing from NF-1 by the absence of neurofibromas and other neural crest tumors. OBSERVATIONS: We describe multiple CLS in 12 patients from three families, each with at least two generations of affected adults. The clinical presentation was consistent within families. In one family, the CLS were accompanied by axillary and inguinal freckling and Lisch nodules. Otherwise, none of the 12 patients had neurofibromas or noncutaneous manifestations of NF-1. CONCLUSIONS: These families provide further evidence that patients may have multiple CLS, with or without axillary freckling or Lisch nodules, and yet not have NF-1. Care must be taken when counseling families with CLS that the diagnosis of NF-1, with its many associated potential problems, is not made erroneously. Studies of the gene mutation(s) of patients with familial multiple CLS are needed to distinguish NF-1 and familial multiple CLS as distinct disorders.

Adult↗
PubMed1992

Preferential mutation of the neurofibromatosis type 1 gene in paternally derived chromosomes.

An interesting feature of neurofibromatosis type 1 (NF1) is its high mutation rate of 1 x 10(-4) per gamete per generation. The molecular basis for frequent NF1 mutation in unknown; the gene is not deletion prone. We have found that in all ten families examined, the apparent new NF1 mutation occurred on the paternally-derived chromosome. The probability of observing this result by chance is less than 0.001 assuming an equal frequency of mutation of paternal and maternal NF1 genes. We hypothesize a role for genomic imprinting that may either enhance mutation of the paternal NF1 gene or confer protection from mutation to the maternal NF1 gene.

Chromosomes, Human↗
PubMed1992

The gene for a novel epidermal antigen maps near the neurofibromatosis 1 gene.

Recently the M17S1 gene, encoding an epidermal antigen thought to play a role in cell adhesion, was mapped to chromosome bands 17q11-q12, placing it in the vicinity of the gene for the genetic disorder neurofibromatosis 1 (NF1). The pleomorphic cutaneous lesions of NF1 and the precedent for other genes being embedded within the NF1 gene prompted us to investigate whether the M17S1 gene mapped near, or within, the NF1 gene. Genetic linkage analyses revealed that M17S1 was tightly linked to NF1 and mapped within the interval bounded by D17S58 and D17S54. Physical mapping of an M17S1 cDNA on somatic cell hybrids, yeast artificial chromosomes, and an NF1 patient with a deletion involving an entire NF1 allele demonstrated that M17S1 is located at least 180 kb centromeric to the NF1 gene. The distance between the genes suggests that M17S1 is unlikely to contribute to the NF1 phenotype since a gross chromosomal rearrangement would be required to disrupt expression of both genes.

Animals↗
PubMed1992

Large de novo DNA deletion in a patient with sporadic neurofibromatosis 1, mental retardation, and dysmorphism.

A mildly dysmorphic, mentally retarded male with neurofibromatosis 1 (NF1) was found to have a de novo deletion of chromosome 17. The deletion occurred on the paternally derived chromosome 17 as shown by the absence of a D17S73 paternal allele. Densitometric analysis indicated that, in addition to the D17S73 locus, the patient has only one copy of four other adjacent loci. The deletion involved the loci D17S120, NF1, D17S57, D17S115, and D17S73 and was estimated to encompass more than 380 kb of DNA. The deletion of the entire paternal NF1 allele argues strongly that this disorder is not caused by the action of an abnormal NF1 protein. The extent of the deletion suggests that the mental retardation and dysmorphism of this patient may result from a deletion involving both the NF1 gene and contiguous genetic material.

Abnormalities, Multiple↗
PubMed1991

Molecular analysis of a patient with neurofibromatosis 1 and achondroplasia.

The gene for von Recklinghausen neurofibromatosis (NF1) is on proximal 17q; the location of the gene for achondroplasia (ACH) is unknown. We have begun a molecular analysis of a patient with mental retardation, NF1 and ACH, a clinical presentation suggestive of a contiguous gene syndrome. In addition, this individual has a 47,XYY chromosome constitution. To define a possible chromosome 17 deletion, we investigated the copy number of DNA sequences linked to NF1 with conventional and pulsed-field gel electrophoresis (PFGE). We found no evidence for a deletion on chromosome 17. These results make it unlikely that this patient harbors a single deletion in the NF1 region causing both NF1 and ACH and suggest different mechanisms for the de novo occurrence of 2 autosomal dominant disorders in this individual.

Achondroplasia↗
PubMed1991

Absence of association of HTLV-I infection with type 1 neurofibromatosis in the United States or Japan.

An HTLV-I tax transgenic mouse model develops a syndrome with similarities to type 1 neurofibromatosis (NF-1). To investigate possible associations between this human retrovirus and NF-1, we have analyzed 67 neurofibromas from Japan (where HTLV-I infection is endemic) and compared them with 21 cases from the United States. We were not able to identify virus in tumor tissue in either group. This suggests that HTLV-I infection is not commonly associated with NF-1.

Amino Acid Sequence↗
PubMed1991

Familial spinal neurofibromatosis: clinical and DNA linkage analysis.

We studied two families with an unusual variant of neurofibromatosis (NF). The first family had spinal neurofibromas and café au lait spots (CLS), the second spinal neurofibromas without CLS. Other signs of NF1 or NF2, such as cutaneous tumors, Lisch nodules, or acoustic tumors, were absent. The inheritance pattern in both pedigrees was consistent with autosomal dominant inheritance. Using genetic linkage analysis with DNA markers tightly linked to the NF1 and NF2 loci, we determined that the likely location for the mutation in the first family was in the NF1 gene with odds of 97:1, whereas the mutation in the second family was excluded from the NF1 locus with odds greater than 100,000:1. Families such as these, in which a defined subset of the NF phenotype is passed on, are important for understanding the functional consequences of particular mutations in the NF genes.

Adolescent↗
PubMed1990

Mitogen accumulation in von Recklinghausen neurofibromatosis.

Most, but not all, patients with von Recklinghausen neurofibromatosis develop tumors (neurofibromas) that contain large numbers of Schwann cells and fibroblasts. To begin to understand the molecular events that contribute to cell proliferation in these benign tumors, we have analyzed extracts of neurofibromas to determine whether they contain mitogens for Schwann cells or fibroblasts, or both. Schwann cell and fibroblast mitogens are present in neurofibroma extracts. All the neurofibromas analyzed contain a Schwann cell mitogen similar to a neuronal cell surface molecule known to stimulate Schwann cell proliferation during normal development; this mitogen also stimulates fibroblast proliferation. Basic fibroblast growth factor is present in 60% of tumors evaluated. Accumulation of mitogenic substances may contribute to the growth of neurofibromas.

Cell Division↗
PubMed1990

Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis.

von Recklinghausen neurofibromatosis (NF1) is a common hereditary disorder characterized by neural crest-derived tumors, particularly benign neurofibromas whose malignant transformation to neurofibrosarcomas can be fatal. The NF1 gene has been mapped to a small region of chromosome 17q, but neither the nature of the primary defect nor the mechanisms involved in tumor progression are understood. We have tested whether NF1 might be caused by the inactivation of a tumor suppressor gene on 17q, analogous to that on chromosome 22 in NF2, by searching for deletions of chromosome 17 in NF1-derived tumor specimens. Both neurofibrosarcomas from patients with "atypical" NF and 5 of 6 neurofibrosarcomas from NF1 patients displayed loss of alleles for polymorphic DNA markers on chromosome 17. However, the common region of deletion was on 17p and did not include the NF1 region of 17q. Since no loss of markers on chromosome 17 was observed in any of 30 benign tumors from NF1 patients, the 17p deletions seen in neurofibrosarcomas are probably associated with tumor progression and/or malignancy. This region contains a candidate gene for tumor progression, p53, which has recently been implicated in the progression of a broad array of human cancers. In a preliminary search for p53 aberrations by direct sequencing of polymerase chain reaction-amplified DNA from 7 neurofibrosarcomas, 2 tumors that contained point mutations in exon 4 of the p53 gene were found, suggesting a role for this gene in at least some neurofibrosarcomas. Thus the formation of malignant neurofibrosarcomas may result from several independent genetic events including mutation of the NF1 gene, whose mechanism of tumorigenesis remains uncertain, and subsequent loss of a "tumor suppressor" gene on 17p, most likely p53.

Base Sequence↗