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S M Pulst

Publications and source records attributed to S M Pulst.

At least 73 records · Page 4Linked to original sources
PubMed1996

Genetic mapping of the spinocerebellar ataxia type 2 gene on human chromosome 12.

The dominant spinocerebellar ataxias are a genetically heterogeneous group of diseases leading to premature death of neurons in the cerebellum and other parts of the nervous system. The mutation causing SCA1 is on human chromosome (CHR) 6p and SCA3 is on CHR 14q. To refine the location of the SCA2 gene on CHR 12q, we performed genetic linkage analysis between the SCA2 locus and nine Ioci (D12S58, D12S78, D12S317, D12S330, D12S353, D12S84, D12S105, D12S79, and PLA2) in three SCA2 families. The highest pairwise lod scores were obtained between SCA2 and D12S84/D12S105 and D12S79. We determined the best order and genetic distances among these loci in ten multigenerational families by multipoint linkage analysis and established the following order: D12S101-D12S58/IGF1- D12S78-D12S317-D12S330/D12S353-D12S84/D 12S105-D12S79-PLA2. Using this genetic map, multipoint linkage analysis placed SCA2 between D12S84/D12S105 and D12S79.

Chromosome Mapping↗
PubMed1996

Presymptomatic diagnosis of neurofibromatosis 2 using linked genetic markers, neuroimaging, and ocular examinations.

Neurofibromatosis 2 (NF2) is an autosomal dominant disorder that causes nervous system tumors and ocular abnormalities such as early-onset lenticular opacities. We assessed the clinical spectrum of NF2 at the time of presymptomatic DNA diagnosis in at-risk first-degree relatives. We studied five multigeneration NF2 families with short tandem repeat markers near the NF2 gene (NF2); gadolinium-enhanced high-resolution magnetic resonance imaging (GE-MRI); and ocular, dermatologic, and neurologic examinations. Eleven of 31 asymptomatic at-risk first-degree relatives were predicted by segregation analysis to be NF2 mutation carriers. Nine of the 11 NF2 mutation carriers were clinically evaluated. Four mutation carriers, including a 7-year-old, had vestibular schwannomas, early-onset cataracts, or both. However, five mutation carriers did not have clinical abnormalities, including a 38-year-old with normal cranial and spinal GE-MRIs and a normal ocular examination. These results indicate that clinical abnormalities can be present in young, but absent in middle-aged, presymptomatic NF2 mutation carriers. By identifying presymptomatic NF2 mutation carriers, DNA diagnosis of NF2 can improve genetic counseling and clinical management, and possibly reduce psychosocial difficulties in at-risk individuals.

Adult↗
PubMed1996

Expression of neurofibromatosis 2 transcript and gene product during mouse fetal development.

Neurofibromatosis 2 (NF2) is an autosomal dominant inherited disorder that predisposes to benign tumors of the nervous system as well as a variety of ocular abnormalities. In contrast to NF1, NF2 is associated with only minor developmental abnormalities. The human NF2 gene encodes a tumor suppressor protein, termed schwannomin or merlin, which is a member of a superfamily of proteins thought to link cytoskeletal elements to cell membrane components. To determine the pattern of NF2 gene expression in mouse embryos, we sequenced the mouse NF2 gene and used in situ hybridization and antischwannomin antibodies to determine the developmental expression of the NF2 gene. Schwannomin was detected in most differentiated tissues but was undetectable in undifferentiated tissues. In particular, schwannomin was not detectable in mitotic neuroepithelial cells, the perichondrium, the liver, the neocortex, and the ventricular zone of the developing cerebral cortex. In the heart, expression was observed in all developmental stages beginning on embryonic day 8. In the eye, which shows developmental abnormalities in NF2 patients, expression was detected in the cells of the lens and in the pigment epithelium but weakly detected in retinal neurons. The most striking example of tightly regulated NF2 expression was observed in cells migrating from the ventricular zone to the cortical plate on embryonic days 15 and 16. Only cells in the intermediate zone expressed schwannomin, indicating that schwannomin may play an important role in cellular migration.

Amino Acid Sequence↗
PubMed1995

A 163-bp deletion in the neurofibromatosis 2 (NF2) gene associated with variant phenotypes [corrected].

We have analyzed cDNA from a 46-year-old atypical neurofibromatosis type 2 (NF2) patient who had lumbar tumors, cataract and schwannomas of peripheral nerves but no vestibular schwannomas, and have identified a 163-bp deletion in the NF2 transcript. The deletion is predicted to remove 54, alter 15 and add four extra amino acids at the C-terminus of the NF2-gene product. The same deletion was found in her two daughters and in a 3-year-old grandson. Bilateral vestibular schwannomas were detected in the two asymptomatic daughters, whereas no abnormality was found in the grandson.

Adult↗
PubMed1995

Construction and utility of a human chromosome 22-specific Fosmid library.

We have previously demonstrated the capability of the Fosmid vector based on Escherichia coli F-factor replicon to stably propagate cosmid-sized human genomic DNA fragments. Using the Fosmid vector, we have constructed and arrayed a 10 x human chromosome 22-specific library, partly by picking human positive clones from a total Fosmid library constructed using DNA from human-hamster hybrid cell line containing human chromosome 22, and partly by using flow-sorted chromosomal DNA. The clones and physical contig maps of the clones in the library will serve as a valuable resource for detailed analysis of the chromosome by providing reliable materials for high resolution mapping and sequencing. In order to efficiently build physical maps for the chromosomal regions of interest spanning several hundred kilobases to a megabase, it is necessary to rapidly identify subsets of the Fosmid clones from the library that cover such regions. In this report, we describe a method of using random amplification products derived from YAC clones to rapidly identify a subset of Fosmid clones that cover a specific genomic subregion.

Animals↗
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↗
PubMed1995

Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity, and variety.

OBJECTIVE: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder leading to various tumors of the CNS, with vestibular schwannomas being the hallmark of the disease. We have observed multiple asymptomatic spinal lesions in patients who have a single symptomatic spinal tumor. Accordingly, we studied the frequency, multiplicity, and variety of spinal tumors in all patients with NF2 to determine what is characteristic of the disease. SUBJECTS AND METHODS: MR images of the entire spinal canal were made in 73 patients aged 4-69 years with NF2. The number, location, morphology, signal characteristics, and contrast medium uptake of the spinal tumors as seen on MR images were recorded and analyzed. Histopathologic proof of 22 spinal tumors was obtained in 19 patients. RESULTS: Spinal tumors were found on MR images in 89% of the patients studied. No location in any part of the spine was preferred. MR imaging showed intramedullary tumors in 24 patients (33%) (three ependymomas pathologically proven). Extradural and intradural extramedullary tumors were found on MR imaging in the cervical spine of 36 patients, the thoracic spine of 40 patients, and the lumbar spine of 49 patients. These tumors were meningiomas, schwannomas, or neurofibromas, three categories that could not be differentiated on the basis of the neuroradiologic findings, with ten schwannomas, seven meningiomas, and two neurofibromas pathologically proven. Extradural extramedullary tumors were found on MR imaging in the cervical spine of 12 patients, the thoracic spine of five patients, and the lumbar spine of 18 patients. A syrinx associated with a tumor was found in two patients. In 19 patients the variety of tumor types was confirmed by histologic examination. CONCLUSION: Patients with NF2 frequently have spinal tumors, which are often multiple and of various histologic types. The presence of multiple and different pathologic types of spinal tumors is highly suggestive of NF2.

Adolescent↗
PubMed1994

Differential expression and tissue distribution of type I and type II neurofibromins during mouse fetal development.

Mutations in the NF1 gene may cause developmental abnormalities and the formation of a variety of tumors of neural crest origin in humans. The NF1 gene codes for a large protein, neurofibromin (nf), which is structurally and functionally related to yeast and human ras-GTPase-activating proteins (ras-GAPs). Recently, two transcripts coding for type I and type II nf with different ras-GAP activity have been identified. Since ras proteins do not appear to be significantly regulated during mouse development, we examined if differential expression of neurofibromins may provide evidence for a role of nfs in regulating ras-mediated cell proliferation and differentiation. Nfs were expressed as early as E8. At E11 a marked increase of NF1 transcripts occurred and was associated with expression of nfs in all tissues. Type I and type II nfs each showed a different time course of expression and tissue localization, with type II nf present mainly from E8 through E10, although in the heart type II nf was present at E12. In some tissues such as heart and dorsal root ganglia rapid increases and decreases of nfs were detected related to differentiation of these tissues. These results are consistent with a role of nfs in regulating ras-mediated cell proliferation and differentiation during development and support distinct functional roles for type I and type II nfs.

Animals↗
PubMed1994

Mutations of the neurofibromatosis type 2 gene and lack of the gene product in vestibular schwannomas.

Schwannomas are common tumors of the nervous system and are frequently found in patients with neurofibromatosis (NF) 2. Although loss of heterozygosity in NF2 tumors suggests that the NF2 gene functions as a tumor suppressor gene, the NF2 gene shows amino acid sequence homology to structural proteins in one of which dominantly acting mutations have been described. We performed a mutational analysis in 30 vestibular schwannomas and examined the effect of mutations on the NF2 protein. We detected 18 mutations in 30 vestibular schwannomas of which seven contained loss or mutation of both NF2 alleles. Most mutations were predicted to result in a truncated protein. Mutational hot spots were not identified. Immunocytochemical studies using antibodies to the NF2 protein showed complete absence of staining in tumor Schwann cells, whereas staining was observed in normal vestibular nerve. These data indicate that loss of NF2 protein function is a necessary step in schwannoma pathogenesis and that the NF2 gene functions as a recessive tumor suppressor gene.

Amino Acid Sequence↗
PubMed1994

Alternative transcripts in the mouse neurofibromatosis type 2 (NF2) gene are conserved and code for schwannomins with distinct C-terminal domains.

Mutations in the neurofibromatosis type 2 (NF2) gene predispose individuals to the development of nervous system tumors and ocular abnormalities. The NF2 gene product, schwannomin, is a member of a superfamily of proteins thought to link cytoskeletal elements to cell membrane components. These proteins share significant homologies in the N-terminal and alpha-helical domains, but diverge in the C-terminus. During our efforts to characterize mouse NF2 transcripts, we identified four different transcripts by cDNA analysis and reverse-transcribed PCR that contained different sequences in the 3' end of the coding sequences. In human cell lines three isoforms encoding two distinct schwannomins were detected. The mouse and human transcripts containing 61 and 60 bp inserts, respectively, have not been previously described. The isoforms encode schwannomins with significantly altered C-termini and were expressed at different relative levels in adult mouse tissues and during mouse embryogenesis. These results suggest that schwannomin isoforms have distinct functional roles and predict the existence of human mutations involving the C-terminus of schwannomin.

Amino Acid Sequence↗
PubMed1993

Linkage of familial Alzheimer disease to chromosome 14 in two large early-onset pedigrees: effects of marker allele frequencies on lod scores.

Alzheimer disease (AD) is a devastating neurodegenerative disease leading to global dementia. In addition to sporadic forms of AD, familial forms (FAD) have been recognized. Mutations in the amyloid precursor protein (APP) gene on chromosome (CHR) 21 have been shown to cause early-onset AD in a small number of pedigrees. Recently, linkage to markers on CHR 14 has been established in several early-onset FAD pedigrees. We now report lod scores for CHR 14 markers in two large early-onset FAD pedigrees. Pairwise linkage analysis suggested that in these pedigrees the mutation is tightly linked to the loci D14S43 and D14S53. However, assumptions regarding marker allele frequencies had a major and often unpredictable effect on calculated lod scores. Therefore, caution needs to be exercised when single pedigrees are analyzed with marker allele frequencies determined from the literature or from a pool of spouses.

Alleles↗
PubMed1993

Familial meningioma is not allelic to neurofibromatosis 2.

Meningiomas frequently lose parts of chromosome 22 (CHR 22), suggesting that a meningioma tumor-suppressor gene is located on CHR 22. Since meningiomas are common in neurofibromatosis 2 (NF2) and the NF2 gene is mapped to CHR 22, the NF2 gene is a candidate for the meningioma gene. To determine whether NF2 and familial meningioma are allelic mutations, we studied a family with multiple meningiomas and ependymomas in two generations using genetic linkage analysis with DNA markers known to flank the NF2 locus. Multipoint linkage analysis resulted in location scores < -2 for a region of 15 cM including the NF2 region. These results support the existence of a familial meningioma locus that is distinct from the NF2 locus.

Alleles↗
PubMed1993

Neurofibromatosis 2 in the pediatric age group.

Bilateral acoustic neurofibromatosis or neurofibromatosis 2 (NF2) is an autosomal dominant disease predisposing to the formation of multiple tumors in the central and peripheral nervous system. Vestibular schwannomas (VSs) are considered to be the hallmark of the disease, but other tumors and ocular findings occur as well. In patients that do not carry the NF2 mutation, VSs usually occur in the fifth or sixth decade of life. VSs in patients with NF2 are often bilateral and become symptomatic in the third or fourth decade of life. In order to define the early manifestations of NF2, we examined nine children who either had one parent with NF2 or had multiple skin or spinal tumors suggestive of NF2. In addition to neurological, dermatological, and ocular examinations, all patients were studied by gadolinium-enhanced magnetic resonance imaging of the brain and spine. None of the children exhibited symptoms or signs due to VSs. However, VSs were detected during the neuroradiological work-up in six children. Seven children developed symptoms or signs due to skin or spinal tumors. Slit lamp examination detected cataracts in four patients as young as 10 years of age. The diagnosis of NF2 in the pediatric age group requires a high degree of suspicion and should be considered in children with multiple central nervous system or skin tumors without cafe-au-lait spots or Lisch nodules. Because VSs are unlikely to produce the signs seen at the time of admission, careful examination of the skin and eyes is necessary and should be followed by gadolinium-enhanced magnetic resonance imaging of the brain and spine. First-degree relatives need to be examined as well.

Adolescent↗