Human mutations

The newest molecular addition to Cl- channels are bestrophins [5]. There are four different bestrophin isoforms in humans. Mutations in Bestl cause Best macular dystrophy, hence their name. All four isoforms induce chloride currents when expressed heterologously. Although they show a dependence on intracellular calcium, their biophysical properties differ from Ca-activated chloride currents typically observed in native cells. Mutagenesis experiments changed the activation of currents and induced slight changes in ion selectivity, lending support to the hypothesis that bestrophins themselves are Cl- channels. 

In humans, mutations in the a2(VIII) gene result in corneal endothelial dystrophies, Fuchs endothelial dystrophy (FECD), and posterior polymorphous comeal dystrophy (PPCD). Recently, it was reported that the mutation L450W in COL8A2 causes an early-onset subtype of Fuchs corneal dystrophy. ... 

Ramirez, A., Faupel, J., Goebel, I., Stiller, A., Beyer, S., Stockle, C., Flasan, C., Bode, U., Kornak, U., and Kubisch, C. (2004) Identification of a Novel Mutation in the Coding Region of the Grey-Lethal Gene OSTMl in Human Malignant Infantile Osteopetrosis. Human Mutations 23, 471-476. 

Notaro, R., Afolayan, A., Luzzatto, L. (2000) Human mutations in glucose 6-phosphate dehydrogenase reflect evolutionary history. FASEB J. 14, 485-494. 

A similar editing process prevents isoleucyl-, leucyl-, and methionyl-tRNA synthetases from attaching L-homocysteine to tRNAs 260-263 In this case, instead of hydrolysis the editing site catalyzes conversion of the homocysteinyl-adenylate into homocysteine lactone. Naturally occurring mutations in tRNA molecules can sometimes have serious consequences. For example, a human mutation is responsible for a fragile mitochondrial isoleucine tRNA and serious cardiomyopathy and opthalmophegia (see also Box 18-B).263a... 

Mice knocked out for CD2-associated protein (CD2AP) also develop nephrotic syndrome and renal failure with histologic appearance of FSGS (S14). CD2AP is an 80-kDa protein interacting with the cytoplasmic domain of nephrin (Section 2.5). Human mutation of the gene for CD2AP has not been described yet. 

Cronin MT, Ficini RV, Kim SM,Masino RS,Wespi RM, MiyadaCG (1966) Human Mutation... 

If transposons cause human mutation in significant numbers, this will necessitate some revision in mutagenicity testing. The mechanisms of transposition may be more akin to those of crossing-over. It is quite likely that many chemicals that induce base substitutions or chromosomal breaks may have little influence on transpo son-induced mutation, whereas other chemicals may affect transposons specifically. In this regard, it is interesting that some transposons act exclusively in germ cells, but not in somatic cells. 

But estimation of human mutation rates is only half the problem. It is also necessary to assess the impact of mutation on human welfare.319... 

Suppose we have estimated (by such methods as were discussed in Chapter 6) that the overall human mutation rate has been increased by a specified percentage. To make a rational assessment of the impact of the increase, we would need to know ... 

Hook, E.B. Monitoring human mutations and consideration of a dilemma posed by an apparent increase in one... 

Harcourt, A.R. Lehmann, S. Stevens, and B.A. Bridges. Ataxia telangiectasia a human mutation with abnormal radiation sensitivity. Nature 258 427-429, 1975. 

King, C.M., Bristow-Craig, H.E., Gillespie, E.S., and Barnett, Y.A. 1997. In vivo antioxidant status, DNA damage, mutation and DNA repair capacity in cultured lymphocytes from healthy 75- to 80-year-old humans. Mutat Res/Fund Mol Mech Mut 377(1) 137-147. 

Cronin, M.T., Fucini, R.V., Kim, S.M., Masino, R.S., Wespi, R.M. and Miyada, C.G. (1996) Cystic Fibrosis mutation detection by hybridization to hght-generated DNA probe arrays. Human Mutation, 7 244-255. 

Oberacher, H. et al. Increased forensic efficiency of DNA fingerprints through simultaneous resolution of length and nucleotide variability by high-performance mass spectrometry. Human Mutat. 2008, 29, 427-432. 

Gross, E. et al. Allelic loss analysis by denaturing high-performance liquid chromatography and electrospray ionization mass spectrometry. Human Mutat. 2007, 28, 303-311. 

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