Linked Recessive Mutations

Normal females have two copies of the X chromosome, so they usually require two copies of the mutation to express the disease. However, because X inactivation is a random process, a heterozygous female will occasionally express an X-linked recessive mutation because, by random chance, most of the X chromosomes carrying the normal allele have been inactivated. Such females are termed manifesting heterozygotes. Because they usually have at least a small population of active X chromosomes carrying the normal allele, their disease expression is typically milder than that of a hemizygous male. 

Both types of muscular dystrophy are X-linked recessive mutations, making a gain-of-function highly unlikely for either type (choice A). 

The incidence of Duchenne muscular dystrophy in North America is about 1/3,000 males. On the basis for this figure, what is the gene frequency of this X-linked recessive mutation ... 

Severe combined immune deficiency (SCID) is a rare inherited disorder in which multiple components of the immune system are affected. About 50% of SCID cases are caused byX-linked recessive mutations in the gene encoding a subunit of a receptor for interleukins 2,4,... 

Carbon tetrachloride was not mutagenic in bacteria. It induced intra-chromosomal and mitotic recombination but not aneuploidy in Saccharomyces cerevisiae, aneuploidy was detected in another single study in Aspergillus nidulans. In vivo, in a single study with Drosophila melanogaster, no sex-linked recessive mutations were observed. 

D has been active in many different short-term genetic assays, including DNA damage and repair, mutations in yeast and human cells, sex-linked recessive mutations in fruit flies, and chromosome aberrations in vitro. 

Thioacetamide induced an increase in sex-linked recessive mutations in Drosophila. It was non-mutagenic in the SalmonellalAmes mutagenicity assay, and in the Escherichia coli recombination assay. Protein synthesis in mouse hepatoma (MH-134), but not in L-929 cells, was enhanced by adding thioacetamide. 

X-linked recessive mutations would readily be detected in XY or XO cells. The azaguanine-resistant mutants in the hamster cells which we have studied (Chu et al.y 19696) are hypothesized to be X-linked. The particular cell line, V79, was originally derived from the lung tissue of a male animal (Ford and Yerganian, 1958). 

In the X-linked recessive mutations in man and several other species often designated as the testicular feminization or androgen-insensitivity syndrome, complete or partial resistance to endogenous androgens, and to exogenous testosterone or dihydrotesterone, is man-... 

TK or HPRT forward mutation assays in cultured mammalian ceils Drosophila sex-linked recessive lethal assay... 

Insect systems Drosophila melanogaster (sex-linked recessive lethal test) Recessive lethal mutation + Velazquez et al. 1984... 

Primary lysosomal hydrolase defects. Two-thirds of the lysosomal storage diseases involve defects in genes that code for acid hydrolases. Table 41-2 lists 29 defects that have been defined so far. They have an autosomal recessive mode of inheritance, except for Hunter s syndrome and Fabry s disease, where the mode is X-linked recessive. The defective genes have been identified and mutations have been defined for nearly all. The nervous system is involved in most. Many of the disorders show a wide range of clinical severity, which may range from death in early childhood to a moderate disability in adulthood. 

Glucose-6-phosphate dehydrogenase (G6PD) deficiency in red blood cells X-linked recessive inheritance many specific mutations Common variants mild deficiency variant in African Americans, moderately severe deficiency variant in Caucasians of Mediterranean descent Frequency 1/10 males 1/100 males, African American and Mediterranean, respectively... 

X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. Families with an X-linked recessive disorder often have affected males, but rarely affected females, in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission). 

Menkes disease, an X-linked recessive condition, is caused by mutations in the gene encoding a Cu efflux protein. Cells from an affected individual accumulate high concentrations of Cu " that cannot be released from the cell. The symptoms result from functional Cu deficiency inasmuch as Cu absorbed from the intestine becomes trapped in the intestinal epithelial cells and delivery to other tissues is inadequate. 

As in X-linked recessive inheritance, male-male transmission of the disease-causing mutation is not seen Fig 11-1-8). 

Because males have only one X chromosome, gene frequency estimation for X-Hnked traits differs from that of autosomal traits. Consider hemophilia A (Chapter 1), which is an X-linked recessive disease. If a male s X chromosome has a factor VIII mutation, he will have hemophilia A. If his X chromosome does not have the mutation, he will not develop the disease. Thus, the gene frequency for hemophilia A is obtained simply by counting the proportion of affected males in the population (i.e., the proportion of X chromosomes containing the mutation). Approximately one in 10,000 males has hemophilia A. Thus, the gene frequency for this disease, q, is 1/10,000. 

Answer A. Because males have only a single X chromosome, each affected male has one copy of the disease-causing recessive mutation. Thus, the incidence of an X-linked recessive disease in the male portion of a population is a direct estimate of the gene frequency in the population. 

Nephrogenic diabetes insipidus (NDI) is characterized by renal tubular resistance to the antidiuretic effect of arginine vasopressin (AVP). NDI may be inherited as an autosomal dominant or X-linked recessive disorder. The autosomal dominant form of NDI results from mutations of the aquaporin 2 gene (AQP2). AQP2 encodes a water channel of the renal collecting duct. Its disruption causes autosomal dominant NDI (113,114) and occasionally recessive forms of the disease. 

Sex-linked recessive lethal mutations were not produced in Drosophila fed ethanol solution containing 50 ppm 1,2-diphenylhydrazine for 3 days (Yoon et al. 1985). No oral genotoxicity studies of 1,2-diphenylhydrazine in mammals were located. 

Sex-linked recessive Drosophila melanogaster/ lethal mutation feeding... 

Vogel, E., Blijleven, W.G.H., Kortselius, M.J.H. and Zijlstra, J.A. (1981) Mutagenic activity of 17 coded compounds in the sex-linked recessive lethal test in Drosophila melanogaster, in Progress in Mutation Research, Volume 1 Evaluation of Short-Term Tests Carcinogens (eds F.J. de Serres and J. Ashby), Elsevier, Amsterdam. 

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