A single copy of carbonic anhydrase 2 restores wild-type circadian period to carbonic anhydrase II-deficient mice.

Carbonic anhydrase II (CA-II)-deficient mice have long circadian periods compared to their siblings with normal CA-II levels. The CA-II-deficient mice differ genetically from their siblings at proximal chromosome three, where the mutated carbonic anhydrase 2 gene sits on a small insert of DNA from the DBA/2J strain. The rest of the genome is that of the C57BL/6J strain.

A locus for circadian period of locomotor activity on mouse proximal chromosome 3.

Lengthened circadian period of locomotor activity is a characteristic of a congenic strain of mice carrying a nonsense mutation in exon 5 of the carbonic anhydrase II gene, car2. The null mutation in car2 is located on a DBA/2J inbred strain insert on proximal chromosome 3, on an otherwise C57BL/6J genomic background. Since reducing the size of the congenic region would narrow the possible candidate genes for period, two recombinant congenic strains (R1 and R2) were developed from the original congenic strain.

New quantitative trait loci for the genetic variance in circadian period of locomotor activity between inbred strains of mice.

Provisional quantitative trait loci (QTL) for circadian locomotor period and wheel-running period have been identified in recombinant inbred (RI) mouse strains. To confirm those QTL and identify new ones, the genetic component of variance of the circadian period was partitioned among an F2 intercross of RI mouse strains (BXD19 and CXB07). First, a genomic survey using 108 SSLP markers with an average spacing of 15 cM was carried out in a population of 259 (BXD19 x CXB07)F2 animals.

A mutation at codon 279 (N279K) in exon 10 of the Tau gene causes a tauopathy with dementia and supranuclear palsy.

Recently intronic and exonic mutations in the Tau gene have been found to be associated with familial neurodegenerative syndromes characterized not only by a predominantly frontotemporal dementia but also by the presence of neurological signs consistent with the dysfunction of multiple subcortical neuronal circuitries. Among families, the symptomatology appears to vary in quality and severity in relation to the specific Tau gene mutation and often may include parkinsonism, supranuclear palsies, and/or myoclonus, in addition to dementia. We carried out molecular genetic and neuropathological studies on two patients from a French family presenting, early in their fifth decade, a cognitive impairment and supranuclear palsy followed by an akinetic rigid syndrome and dementia.

Cloning and characterization of a novel human clathrin heavy chain gene (CLTCL).

An exon representing a novel clathrin heavy chain gene (CLTCL) was isolated during gene identification studies and transcription mapping of human chromosome 22. Isolation and sequencing of cDNA clones corresponding to this exon revealed extensive similarity of the predicted amino acid sequence of this gene product to those of clathrin heavy chain genes of other species. Northern blot analysis has revealed an apparent developmental expression pattern of an approximately 6-kb mRNA.

An expression-independent catalog of genes from human chromosome 22.

To accomplish large-scale identification of genes from a single human chromosome, exon amplification was applied to large pools of clones from a flow-sorted human chromosome 22 cosmid library. Sequence analysis of more than one-third of the 6400 cloned products identified 35% of the known genes previously localized to this chromosome, as well as several unmapped genes and randomly sequenced cDNAs. Among the more interesting sequence similarities are those that represent novel human genes that are related to others with known or putative functions, such as one exon from a gene that may represent the human homolog of Drosophila Polycomb.

In-frame deletion in the proteolipid protein gene of a family with Pelizaeus-Merzbacher disease.

We describe an in-frame deletion of parts of exons 3 and 4 of the proteolipid protein gene (PLP), with all of the intervening sequence, in a 3-generation family with Pelizaeus-Merzbacher disease. The mutation removes 49 amino acids of the PLP.

A 500-kilobase region containing the tuberous sclerosis locus (TSC1) in a 1.7-megabase YAC and cosmid contig.

A complete overlapping clone map of a 1.7-Mb region from DBH to D9S67 that includes the TSC1 candidate region has been constructed. The map includes YAC and cosmid clones, contains STS approximately every 50 kb on average, and establishes the order of five previously unordered loci.

Mapping of the human TATA-binding protein gene (TBP) to chromosome 6qter.

TATA-binding protein (TBP) is a general transcription factor involved in transcriptional initiation. We have used oligonucleotide primers flanking a polymorphic stretch of 38 glutamine codons in the 5' coding region of the TBP gene to genetically map this gene. We report the location of the human TBP gene to be at 6qter.

Peripherin gene is linked to keratin 18 gene on human chromosome 12.

Peripherin is a neuron-specific intermediate filament (IF) protein, found primarily in phylogenetically old regions of the nervous system. Whereas other neuronal IF genes have only two to three introns and are scattered in the genome, the peripherin gene (PRPH) has a complex intron-exon structure like nonneuronal IF genes that are clustered in tandem arrays, e.g.

Genetic linkage studies in autosomal dominant parkinsonism: evaluation of seven candidate genes.

Linkage studies were performed in three families (A, B, and C) with autosomal dominantly inherited parkinsonism affecting multiple members in three generations. Affected individuals exhibited the cardinal signs and symptoms of Parkinson's disease, with a mean age of onset of 51, 62, and 61 years in Families A, B, and C, respectively. Parkinsonian symptoms responded to L-dopa treatment, and an [18F]6-fluoro-L-dopa positron emission tomography scan in 1 affected member of Family B showed decreased striatal uptake typical of Parkinson's disease.

Mutational analysis of patients with neurofibromatosis 2.

Neurofibromatosis 2 (NF2) is a genetic disorder characterized by the development of multiple nervous-system tumors in young adulthood. The NF2 gene has recently been isolated and found to encode a new member of the protein 4.1 family of cytoskeletal associated proteins, which we have named merlin.

Hereditary variations in monoamine oxidase as a risk factor for Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder caused by loss of dopaminergic neurons in the brainstem. Recent studies suggest that several genes may have a role in determining individual susceptibility to this disease, and the degradative enzyme monoamine oxidase (MAO) has been implicated in the disease process. Wide differences in activity levels for both forms of this enzyme (MAO-A and MAO-B) exist in the human population, and levels of both are genetically determined.

Exon scanning for mutation of the NF2 gene in schwannomas.

Family studies and tumor analyses have combined to indicate that neurofibromatosis 2 (NF2), a disorder characterized by multiple benign tumors of the nervous system, and sporadic non-inherited forms of the same tumor types are both caused by inactivation of a tumor suppressor gene located in 22q12. Recently, the gene encoding merlin, a novel member of a family of cytoskeleton-associated proteins, was identified as the NF2 tumor suppressor. To facilitate the search for merlin mutations, we have defined the exon-intron boundaries for all 17 NF2 exons, including one subject to alternative splicing.

The murine NF2 homologue encodes a highly conserved merlin protein with alternative forms.

The recently isolated gene for neurofibromatosis type 2 (NF2) encodes a 595 amino acid protein, named merlin, which is related to the cytoskeleton-associated proteins moesin, ezrin and radixin. To identify evolutionarily conserved regions and to provide sequence information necessary for the establishment of a mouse model for NF2, we have determined the cDNA sequence of the mouse NF2 tumor suppressor gene, and mapped it in the mouse genome. Mouse merlin is a 596 amino acid protein, 98% identical to human merlin, but one amino acid longer due to the insertion of a proline residue near the C-terminus.

Mutations in transcript isoforms of the neurofibromatosis 2 gene in multiple human tumour types.

The neurofibromatosis 2 gene (NF2) has recently been isolated and predicted to encode a novel protein related to the moesin-ezrin-radixin family of cytoskeleton-associated proteins. Here we describe a novel isoform of the NF2 transcript that shows differential tissue expression and encodes a modified C terminus of the predicted protein. Mutations affecting both isoforms of the NF2 transcript were detected in multiple tumour types including melanoma and breast carcinoma.

Isolation of genes from complex sources of mammalian genomic DNA using exon amplification.

Modifications to exon amplification have been instituted that increase its speed, efficiency and reliability. Exons were isolated from target human or mouse genomic DNA sources ranging from 30 kilobases (kb) to 3 megabases (Mb) in complexity. The efficiency was dependent upon the amount of input DNA, and ranged from isolation of an exon for every 20 kb to an exon for every 80 kb of target genomic DNA.

DNA diagnosis of neurofibromatosis 2. Altered coding sequence of the merlin tumor suppressor in an extended pedigree.

Objective: To define the DNA mutation causing neurofibromatosis 2 (NF2), a severe genetic disorder involving the development of multiple nervous system tumors in adulthood, in a large, well-studied NF2 pedigree previously used to chromosomally map and to isolate the disease gene.

Design: Single-strand conformational polymorphism (SSCP) and DNA sequence analysis of the NF2 gene amplified from affected and unaffected family members.

Participants: Affected, unaffected, and at-risk members of a large pedigree segregating NF2, an autosomal dominant disorder caused by inactivation of the merlin tumor suppressor encoded in chromosome band 22q12.

Myelin protein zero gene mutated in Charcot-Marie-tooth type 1B patients.

Autosomal dominant of Charcot-Marie-Tooth disease (CMT), whose gene is type 1B (CMT1B), has slow nerve conduction with demyelinated Schwann cells. In this study the abundant peripheral myelin protein zero (MPZ) gene, MPZ, was mapped 130 kb centromeric to the Fc receptor immunoglobulin gene cluster in band 1q22, and a major MPZ point mutation was found to cosegregate with CMT1B in one large CMT1B family. The MPZ point mutation in 18 of 18 related CMT1B pedigree 1 patients converts a positively charged lysine in codon 96 to a negatively charged glutamate.

Localization of the gene for familial dysautonomia on chromosome 9 and definition of DNA markers for genetic diagnosis.

Familial dysautonomia (DYS), the Riley-Day syndrome, is an autosomal recessive disorder characterized by developmental loss of neurons from the sensory and autonomic nervous system. It is limited to the Ashkenazi Jewish population, where the carrier frequency is 1 in 30. We have mapped the DYS gene to chromosome 9q31-q33 by linkage with ten DNA markers in 26 families.

Onset symptoms in 510 patients with Huntington's disease.

The onset of Huntington's disease (HD) is preceded or accompanied by events and symptoms which contribute to the natural history of the disease. Data obtained from the first 510 completed 'Questionnaires for Affected Individuals', recorded by the National Huntington's Disease Research Roster (NHDRR) were analysed. The following features were evaluated: (1) neurological and psychiatric onset symptoms; (2) the precipitating effect of stressful events and drugs; (3) the modification after onset of smoking and alcohol consumption.

A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor.

Neurofibromatosis 2 (NF2) is a dominantly inherited disorder characterized by the occurrence of bilateral vestibular schwannomas and other central nervous system tumors including multiple meningiomas. Genetic linkage studies and investigations of both sporadic and familial tumors suggest that NF2 is caused by inactivation of a tumor suppressor gene in chromosome 22q12. We have identified a candidate gene for the NF2 tumor suppressor that has suffered nonoverlapping deletions in DNA from two independent NF2 families and alterations in meningiomas from two unrelated NF2 patients.