Pathogenic mutations

Most, and possibly all of these changes result from the tissue accumulation of phytanic acid. Phytanic is of dietary origin exclusively, and dietary restriction of phytanic and plasmapheresis are of clinical benefit. The defective gene and pathogenic mutations have been identified. The clinical manifestations can also be mimicked by defects of PEX7. 

Myopathies have been described in several sporadic cases with lactic acidosis, cytochrome oxidase (COX)-positive RRF in muscle, and isolated complex I deficiency, and have been attributed to various pathogenic mutations in ND genes. The sporadic nature of these myopathies suggests that the ND mutations are de novo, arising spontaneously in myogenic stem cells after germ-layer differentiation (somatic mutations) [14]. 

Pathogenic mutations in the prion protein gene cause inherited prion disease 793... 

How pathogenic mutations in PRNP cause prion disease has yet to be resolved. However, in most cases the mutation is thought to lead to an increased tendency of PrPc to form PrPSc, although there is evidence to suggest that this may not be solely attributable to decreased thermodynamic stability of mutated PrPc. Experimentally manipulated mutations of the prion gene can lead to spontaneous neurodegeneration without the formation... 

Tsien, R. Y., and Lenardo, M. J., 2000, Fas pieassodation required for apoptosis signahng and dominant inhibition by pathogenic mutations. Science 288 2354-2357. 

Fish odour syndrome is an autosomal recessive disease. Mutations have been found in the FM03 gene. Molecular genetic analysis can therefore be used as a diagnostic test. Many pathogenic mutations have been described. The defect should be documented in patients with trimethylaminuria at the metabolite level and the diagnosis confirmed at the molecular genetic level. This chapter describes the available tests at the metabolite level. 

A series of point mutations as well as expansion of the octapeptide repeatss account for the various diseases, which have an autosomal dominant inheritance. At least 23 pathogenic mutations have been... 

Table 1. Selected pathogenic mutations in GC1 (Additional mutations can be found in (Hanein et al., 2004)). LCA1, Leber congenital amaurosis type 1 ar, autosomal recessive ad, autosomal dominant RP, retinitis pigmentosa CORD, cone-rod dystrophy IRP, juvenile isolated RP fs, frameshift mis, missense splice, splice site mutation non, nonsense mutation...

Figure 9. The structure of GCAP3 (Stephen et at., 2006). Residues that correspond to pathogenic mutations in GCAP1, the structure of which is unknown, are shown in yellow with the side chains. Ca2+ is shown as yellow spheres. Molecular graphics representations were created with PYMOL (Warren L. DeLano The PyMOL Molecular Graphics System. DeLano Scientific LLC, San Carlos, CA, USA. http //www.pymol.org) (See Colour Plate 9)...

M4. Manfredi, G., Gupta, N., Vazquez-Memije, M. E., Sadlock, J. E., Spinazzola, A., De Vivo, D. C., and Schon, E. A., Oligomycin induces a decrease in the cellular content of a pathogenic mutation in the human mitochondrial ATPase 6 gene. J. Biol. Chem. 274, 9386-9391 (1999). 

Y4. Yasukawa, T., Suzuki, T., Ueda, T., Ohta, S., and Watanabe, K., Modification defect at anticodon wobble nucleotide of mitochondrial tRNALeu(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. J. Biol. Chem. 275, 4251-4257 (2000). 

Tan EK, Shen H, Tan JM, Lim KL, Fook-Chong S, Hu WP, Paterson MC, Chandran VR, Yew K, Tan C, Yuen Y, Pavanni R, Wong MC, Puvan K, Zhao Y (2005b) Differential expression of splice variant and wild-type parkin in sporadic Parkinson s disease. Neurogenetics 6 179-184 Tan EK, Skipper LM (2007) Pathogenic mutations in Parkinson disease. Hum Mutat 28 641-653... 

The familial prion diseases are inherited in an autosomal dominant manner and account for 10-15% of all human prion disease. They include familial CID (fCJD), GSS, and fatal familial insomnia (FH) (reviewed by Gambetti et al., 2003 and by Kong et al., 2003). The familial prion diseases are caused by pathogenic mutations in the PRNP coding sequence. To date, these include 24 mis-sense mutations that result in amino... 

In an Italian family of whom five family members became deaf after aminoglycoside exposure, the nucleotide 961 thymidine deletion associated with a varying number of inserted cytosines in the mitochondrial 12S ribosomal RNA gene was identified as a second pathogenic mutation that could predispose to aminoglycoside ototoxicity (62). Molecular analysis excluded the A1555G mutation in this family. 

Wallace DC, Stugard C, Murdock D, Schurr T, Brown MD. Ancient mtDNA sequences in the human nuclear genome a potential source of errors in identifying pathogenic mutations. Proc Natl Acad Sd USA 1997 94 14900-5. 

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