Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord. Its cause is unknown and it is uniformly fatal, typically within five years. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8, 9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.- to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.

Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis

Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression

An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria

The primary immunodeficiency disorders reflect abnormalities in the development and maturation of cells of the immune system. These defects result in an increased susceptibility to infection; recurrent pyogenic infections occur with defects of humoral immunity, and opportunistic infections with defects of cell-mediated immunity. These two broad categories of illness correspond roughly to defects in the two principal types of immunocompetent cells, B lymphocytes and T lymphocytes. Defective development of B cells results in abnormalities in humoral immunity, whereas defects in the development of T cells cause problems with cellular immunity. When pathogens are taken up by macrophages or dendritic cells, . . .

The Primary Immunodeficiencies

The current status of superoxide dismutase (SOD) is that it is an enzyme with diverse ramifications. This review attempts an understanding of SOD as a structural, functional, and biological entity. Accordingly, the review is in three parts. The first part discusses SOD in terms of protein structure, proceeding from primary to secondary and three-dimensional structure for the three forms of SOD: copper/zinc SOD, manganese SOD, and iron SOD. This is the order of structural knowledge of the enzyme. Iron SOD is an enzyme of prokaryotes and some higher plants. Manganese SOD is an enzyme of prokaryotes and eukaryotes. Copper/zinc SOD is an enzyme of eukaryotes and certain prokaryotes. The evolutionary relationships of the three forms of SOD, the status of the copper/zinc SOD gene in prokaryotes, and the cloning and sequencing of SOD genes are discussed. The second part of the review deals with the catalytic mechanism of SOD in the three forms of the enzyme. Structural and mechanistic conclusions from various spectroscopic studies are critically considered. A detailed picture is given of the active site of copper/zinc SOD. The third part is a review of SOD in the general context of oxygen toxicity. After consideration of the question of superoxide toxicity and superoxide pathology, several areas in which SOD has been investigated or used as a tool in a biochemical, pharmacological, or clinical context are discussed, including population genetics; trisomy 21; development and senescence; the nutritional copper, zinc, and manganese status; hemolysis and anemia; oxygen toxicity in the lung and nervous system; inflammation, autoimmune disease and chromosome breakage, ischemia and degenerative changes; radiation damage; and malignancy. A comprehensive picture is given of measurements of SOD activity in disease states, and the question of superoxide-related disease is considered at several points.

Aspects of the structure, function, and applications of superoxide dismutase

Standard karyotype of the Norway rat, Rattus norvegicus

SOMATIC cell populations can be used for genetic analysis because of the occurrence of parasexual events1. Genetically dilferent genomes can combine into a single cell by spontaneous2 or virally induced3 cell fusion. In the interspecific hybrid combinations so far studied, the parental chromosomes are lost to a variable extent4. Human/mouse hybrids are particularly favourable for genetic analysis because they preferentially segregate the human chromosomes5. The mouse and human enzymes can be distinguished and the mouse and human chromosomes can be identified by the application of recently developed cytological techniques6,7. Linkage relationships can be inferred by the concordant or discordant segregation of human markers. If positive correlation exists between human phenotypes, it can be presumed that the genes are linked to the same chromosome (they are syntenic); and similarly, if positive correlations exist between chromosomes and phenotypes, this provides strong support for the assignment of gene loci for particular phenotypes to particular human chromosomes.

Assignment of Nucleoside Phosphorylase to D-14 and Localization of X-linked Loci in Man by Somatic Cell Genetics

The segregation of the human peptidase-C phenotype in five different series of human-mouse hybrid clones was examined. The chromosome constitution of these hybrids was determined by quinacrine mustard fluorescence, Giemsa banding, and constitutive heterochromatin staining. That the clones could be classified without exception either as human peptidase C positive/ A-1 positive (14 clones), or as peptidase C negative/ A-1 negative (12 clones) indicates that peptidase C can be assigned to the human A-i chromosome. Data from an extensive series of human-mouse clones used provide support for the syntenic association between peptidase C and phosphoglucomutase-1 and by inference a linkage of both to Rh factor group.

https://science.sciencemag.org/content/sci/176/4042/1429.full.pdf

Somatic Cell Genetic Assignment of Peptidase C and the Rh Linkage Group to Chromosome A-1 in Man

Somatic cell hybrids can be used to make gene assignments in man [1, 2]. Mouse/ human hybrids are useful for this purpose for the following reasons: human chromosomes are preferentially lost, mouse and human homologous enzyme phenotypes can be discriminated, and human chromosomes can be identified in the hybrid cells. It is, therefore, possible to make correlations between the individual human chromosomes and specific human enzyme phenotypes using hybrid clones which possess different human chromosome constitutions. In this report, we present evidence for the assignment of the gene specifying the soluble form of malate oxidoreductase decarboxylating (MOD; EC 1.1.1.40) to human chromosome 6, and the genes for peptidase B (Pep B) and lactate dehydrogenase B (LDH B; EC 1.1.1.27) to chromosome 12.

Assignment of the genes for malate oxidoreductase decarboxylating to chromosome 6 and peptidase B and lactate dehydrogenase B to chromosome 12 in man.

Evidence from mouse/human somatic cell hybrids is presented for the synteny of the genes for indophenol oxidase-B (tetrameric) and cytoplasmic malic enzyme (EC 1.1.1.40). Assignment of these two genes to chromosome 6 is further confirmed. The identification of indophenol oxidase-B (tetrameric) as mitochondrial superoxide dismutase is discussed.

Chromosome assignments of genes in man using mouse-human somatic cell hybrids: mitochondrial superoxide dismutase (indophenol oxidase-B, tetrameric) to chromosome 6.

F. Ricciuti

Papers

Standard karyotype of the Norway rat, Rattus norvegicus

Assignment of Nucleoside Phosphorylase to D-14 and Localization of X-linked Loci in Man by Somatic Cell Genetics

Somatic Cell Genetic Assignment of Peptidase C and the Rh Linkage Group to Chromosome A-1 in Man

Assignment of the genes for malate oxidoreductase decarboxylating to chromosome 6 and peptidase B and lactate dehydrogenase B to chromosome 12 in man.

Chromosome assignments of genes in man using mouse-human somatic cell hybrids: mitochondrial superoxide dismutase (indophenol oxidase-B, tetrameric) to chromosome 6.