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

Identification and characterization of the familial adenomatous polyposis coli gene

A gene discovered by positional cloning has been identified as the von Hippel-Lindau (VHL) disease tumor suppressor gene. A restriction fragment encompassing the gene showed rearrangements in 28 of 221 VHL kindreds. Eighteen of these rearrangements were due to deletions in the candidate gene, including three large nonoverlapping deletions. Intragenic mutations were detected in cell lines derived from VHL patients and from sporadic renal cell carcinomas. The VHL gene is evolutionarily conserved and encodes two widely expressed transcripts of approximately 6 and 6.5 kilobases. The partial sequence of the inferred gene product shows no homology to other proteins, except for an acidic repeat domain found in the procyclic surface membrane glycoprotein of Trypanosoma brucei.

https://science.sciencemag.org/content/sci/260/5112/1317.full.pdf

Identification of the von Hippel-Lindau disease tumor suppressor gene.

The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4 + T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele ( CKR5Δ32 ) was identified that is present at a frequency of ∼0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Δ32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.

/pdf/genetic-restriction-of-hiv-1-infection-and-progression-to-18o44bc772.pdf

Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene

Friedreich's ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous systems and the heart. A gene, X25, was identified in the critical region for the FRDA locus on chromosome 9q13. This gene encodes a 210-amino acid protein, frataxin, that has homologs in distant species such as Caenorhabditis elegans and yeast. A few FRDA patients were found to have point mutations in X25, but the majority were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron.

https://science.sciencemag.org/content/sci/271/5254/1423.full.pdf

Friedreich's Ataxia: Autosomal Recessive Disease Caused by an Intronic GAA Triplet Repeat Expansion

Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction

The normal (wild-type) p53 product acts as a suppressor of transformation [1], while mutated p53 proteins may inactivate the wild-type p53 function resulting in cell transformation [2] Mutations of the p53 gene have been found in conjunction with chromosome 17p allelic deletions in many human tumors [3,4]

Detection of p53 Gene Mutations in Human Brain Tumors by Single-strand Conformation Polymorphism Analysis of Polymerase Chain Reaction Products

Allele-specific polymerase chain reaction: A method for amplification and sequence determination of a single component among a mixture of sequence variants

We have developed a simple, sensitive method, single-strand conformation polymorphism (SSCP) analysis, to detect a single nucleotide substitution in a DNA fragment amplified and labeled by the polymerase chain reaction (PCR). Mobility shift of single-stranded DNAs due to their specific conformations on non-denaturing polyacrylamide gel electrophoresis can reveal DNA aberrations. By the PCR-SSCP analysis of DNAs from surgical specimens of human cancers, mutated ras genes (17%) and aberrations of tumor suppressor p53 gene (53%) including loss of one of the two alleles and a mutation in the remaining allele were detected in lung carcinomas and aberrations of both of the p53 and retinoblastoma (RB) genes were detected exclusively in advanced hepatocellular carcinomas.

Youichi Suzuki

Papers

Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction

Detection of p53 Gene Mutations in Human Brain Tumors by Single-strand Conformation Polymorphism Analysis of Polymerase Chain Reaction Products

Allele-specific polymerase chain reaction: A method for amplification and sequence determination of a single component among a mixture of sequence variants

Detection of DNA aberrations in human cancers by single-strand conformation polymorphism analysis of polymerase chain reaction products