Pathology and genetics of tumours of the urinary system and male genital organs

https://www.cell.com/cell/pdf/0092-8674(92)90362-G.pdf

Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells

A comprehensive review of genetic association studies.

Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity

Viral replication usually requires that innate intracellular lines of defence be overcome, a task usually accomplished by specialized viral gene products The virion infectivity factor (Vif) protein of human immunodeficiency virus (HIV) is required during the late stages of viral production to counter the antiviral activity of APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G; also known as CEM15), a protein expressed notably in human T lymphocytes When produced in the presence of APOBEC3G, vif-defective virus is non-infectious APOBEC3G is closely related to APOBEC1, the central component of an RNA-editing complex that deaminates a cytosine residue in apoB messenger RNA APOBEC family members also have potent DNA mutator activity through dC deamination; however, whether the editing potential of APOBEC3G has any relevance to HIV inhibition is unknown Here, we demonstrate that it does, as APOBEC3G exerts its antiviral effect during reverse transcription to trigger G-to-A hypermutation in the nascent retroviral DNA We also find that APOBEC3G can act on a broad range of retroviruses in addition to HIV, suggesting that hypermutation by editing is a general innate defence mechanism against this important group of pathogens

Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts

https://www.cell.com/cell/pdf/0092-8674(87)90510-1.pdf

A novel form of tissue-specific RNA processing produces apolipoprotein-B48 in intestine.

The Duchenne muscular dystrophy (DMD) gene has been localized to chromosome Xp21 and codes for a 14-kilobase (kb) transcript and a protein called dystrophin, of relative molecular mass 427,000. Dystrophin is associated with the cytoplasmic face of muscle fibre membranes and its C-terminal domain is thought to mediate membrane attachment. Although N-terminal and central domain structures share common features with other cytoskeletal components, no significant sequence similarity between the C-terminal region of dystrophin and other previously characterized proteins has been described. Here we report that fragments from the C-terminal domain of the DMD complementary DNA detect a closely related sequence which exhibits nucleic-acid and predicted amino-acid identities with dystrophin of approximately 65 and 80%, respectively. The dystrophin-related sequence identifies a 13-kb transcript in human fetal muscle and maps to chromosome 6. Thus, dystrophin may be a member of a family of functionally related large structural proteins in muscle.

An autosomal transcript in skeletal muscle with homology to dystrophin.

DYSTROPHIN-RELATED protein (DRP or 'utrophin'1) is localized in normal adult muscle primarily at the neuromuscular junction2–4. In the absence of dystrophin in Duchenne muscular dystrophy (DMD) patients, DRP is also present in the sarcolemma3–7. DRP is expressed in fetal and regenerating muscle and may play a similar role to dystrophin in early development3,7–9, although it remains to be determined whether DRP can functionally replace dystrophin in adult tissue. Previously we described a 3.5-kilobase complementary DNA clone that exhibits 80 per cent homology to the C-terminal domain of dystrophin10. This sequence identifies a 13-kilobase transcript that maps to human chromosome 6 (refs 2, 11). Antibodies raised against the gene product identify a polypeptide with a relative molecular mass of about 400K in all tissues examined7,8,12. To investigate the relationship between DRP and dystrophin in more detail, we have cloned and sequenced the whole DRP cDNA. Homology between DRP and dystrophin extends over their entire length, suggesting that they derive from a common ancestral gene. Comparative analysis of primary sequences highlights regions of functional importance, including those that may mediate the localization of DRP and dystrophin in the muscle cell.

Primary structure of dystrophin-related protein.

SUMMARY

1. A method, for the starch gel electrophoresis of human nucleoside phosphorylase (NP) is described. Multiple NP isozymes were found in most human tissues and the best resolution of these isozymes was achieved by electrophoresis in a buffer system containing lithium ions.



2. Tissue to tissue variation in the complexity of the NP isozyme patterns and the examination of NP isozymes in relatively young red cells, suggest that a primary isozymic form of human NP is modified in vivo with generation of several secondary isozymes. The slowest isozyme is probably the primary form in all tissues, the secondary isozymes have greater anodal electro-phoretic mobilities. Storage experiments carried out with fibroblasts indicate that in vitro modification of the NP isozyme patterns may also occur.



3. Three electrophoretically different genetically determined variants of NP were found in a survey of red cell lysates from 2178 unrelated individuals; one of them was found twice. Family studies showed that these variants occur in individuals heterozygous for a common allele (NP1) and a variant allele (either NP2, NP3 or NP*) at an autosomal locus.



4. Examination of the NP isozymes in cultured fibroblasts and hair follicle cell extracts obtained from individuals with variant red cell phenotypes suggests that NP has a trimeric structure. In vitro hybridization experiments using a freeze-thaw-NaCl technique with mouse and human liver and with calf spleen and human liver NP support this view.



5. The molecular size of human NP by gel filtration chromatography is c. 84,000.

Inherited variants of human nucleoside phosphorylase.

Several isozymes of adenosine deaminase (ADA) in human red cells can be detected by starch-gel electrophoresis and a number of inherited variants have been described (Spencer, Hopkinson & Harris, 1968). The phenotypes ADA 1, ADA 2-1 and ADA 2 occur in European populations with frequencies of about 0.9, 0.1 and 0.003 respectively, and are due to the two common alleles ADA1 and ADA2, phenotypes ADA 1 and ADA 2 representing the homozygotes and the ADA 2-1 phenotype the heterozygous genotype. Several less common phenotypes of red cell ADA have also been identified and in each case family studies have shown that the variant type represents the heterozygous combination of either ADA1 or ADA2 and a rare variant allele at the same locus (Hopkinson, Cook & Harris, 1969; Dissing & Knudsen, 1969; P. Gerald, 1969, personal communication; Detter et al. 1970). The present paper is concerned with the isozymes of ADA in human tissues other than red cells. The principal technique used was starch-gel electrophoresis and a wide range of tissues has been investigated. The sulphydryl group reactivities of the ADA isozymes in different tissues have also been compared, using the procedure of Hopkinson & Harris (1969)) and molecular size estimates of the various ADA isozymes have been obtained by gel filtration chromatography. I n most tissues isozymes similar to the red cell ADA isozymes were encountered but in many tissues additional isozymic forms were found which differed in electrophoretic behaviour, in sulphydryl group reactivity and also in molecular size from the red cell ADA isozymes. The results suggest that human adenosine deaminase may be determined by several different gene loci.

Yvonne H. Edwards

Papers

A novel form of tissue-specific RNA processing produces apolipoprotein-B48 in intestine.

An autosomal transcript in skeletal muscle with homology to dystrophin.

Primary structure of dystrophin-related protein.

Inherited variants of human nucleoside phosphorylase.

Adenosine deaminase isozymes in human tissues