Splice site mutations

GSH-S deficiency is a more frequent cause of GSH deficiency (HI7), and more than 20 families with this enzyme deficiency have been reported since the first report by Oort et al. (05). There are two distinct types of GSH-S deficiency with different clinical pictures. In the red blood cell type, the enzyme defect is limited to red blood cells and the only clinical presentation is mild hemolysis. In the generalized type, the deficiency is also found in tissues other than red blood cells, and the patients show not only chronic hemolytic anemia but also metabolic acidosis with marked 5-oxoprolinuria and neurologic manifestations including mental retardation. The precise mechanism of these two different phenotypes remains to be elucidated, because the existence of tissue-specific isozymes is not clear. Seven mutations at the GSH-S locus on six alleles—four missense mutations, two deletions, and one splice site mutation—have been identified (S14). 

K9. Kanno, H., Wei, D. C. C., Miwa, S., Chan, L. C., and Fujii, H., Identification of a 5 -splice site mutation and a missense mutation in homozygous pyruvate kinase deficiency cases found in Hong Kong. Blood 82 (Suppl. 1), 97a (1993). 

Hutton, M., Lendon, C. L., Rizzu, P. et al. Association of missense and 5 -splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393 702-705,1998. 

Shown are nonsense, missense, deletion/insertion and splice site mutations. The amino acid changes are predictions in most cases. 

Figure 3. Localisation of mutations in CBP and p300 in RTS patients (panel a) and tumour material (panel b). Indicated are nonsense, missense, deletion/insertion and splice site mutations, (c) Schematic representaion of the Rb-E2F and p53 pathways and the effects of CBP and p300 on these pathways...

Splice site mutation A1280-1305 Cell line Ovary Hetero (Ozdag et al, 2002)... 

Splice site mutation del1089-1095 Cell Une Lymphoid Hetero (Shigeno et al, 2004)... 

Splice-site mutations (choice E) occur at intron-exon boundaries and typically result in the loss of an exon or the inclusion of part of an intron in the coding sequence. Thus, more than a single amino acid -would he altered in a typical splice-site mutation. 

These data emphasize the complex nature of the molecular mechanisms controlling polymorphic DPD activity in vivo. The clinical utility for genetic polymorphism testing to date is not optimal because of its low sensitivity and unknown specificity (28). Overall, it can be remarked that the splice site mutation IVS14+1G>A causes severe, even lethal, 5-FU-related toxicity. Unfortunately, the roles of other polymorphisms in the DPYD gene in the severe 5-FU-related toxicity are not clarified. 

Strasser-Wozak EM, Hattmannstorfer R, Hala M, et al. (1995) Splice site mutation in the glucocorticoid receptor gene causes resistance to glucocorticoid-induced apoptosis in a human acute leukemic cell line. Cancer Res. 55, 348-353. 

A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch Neurol 59 1137-1141... 

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...

D Souza-Li, L, Canaff, L, Janicic, N, Cole, DEC and Hendy, GN, 1998, An acceptor splice site mutation in the calcium-sensing receptor gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, Submitted... 

EA2, similar to FHM1, is an autosomal dominant disorder associated with mutations in the CACNA1A gene, but is clinically quite distinct. EA2 patients experience spontaneous episodes of ataxia (poor muscle coordination) that last for hours to days. In between attacks, patients often experience gaze-evoked or down-beat nystagmus (rapid, involuntary eye oscillations). Approximately 50% of patients experience migraine-like symptoms, and cerebellar atrophy is common (Lorenzon and Beam, 2000). Attacks are often initiated by emotional stress, exercise, or alcohol. Most patients respond well to treatment with acetazolamide (reviewed in (Jen et al., 2004)). EA2 is genetically variable and has been associated with missense, truncation and alternative splice site mutations. 

In the analysis of family pedigrees it is usually possible by inspection of RFLP markers to phase or assign each to a specific chromosome. The array of RFLPs constitutes a haplotype unique to that chromosome. For many disorders, even those for which multiple mutations have been defined, within a given population or ethnic group a few specific mutations usually predominate (14). Generally each is associated with a distinctive haplotype of 2 or more RFLP markers. For example, functionally identical intervening sequence 1 splice site mutations in individuals of Mediterranean and Indian bacl round carry completely different RFLP haplotypes (13). Similarly, two RFLP markers proved use-... 

Schwatze U, Starman BJ, Byers PH (1999) Redefinition of exon 7 in the COLlAl gene of type I collagen by an intron 8 spUce-donor-site mutation in a form of osteogenesis imperfecta influence of intron splice order on outcome of splice-site mutation. Am J Hum Genet 65 336-344... 

Zhuang Y, Weiner AM. A compensatory base change in U1 42. snRNA suppresses a 5 splice site mutation. Cell 1986 46 827-835. 

A number of other mutations have been identified that result in ffameshifls and premature terminations. Within GPIIb, a large DNA deletion resulting in a prerrrature termination in intron 1 has been identified in patient KW and a deletion and premature termination in exon 15 caused by a splice site mutation has been identified in kindreds of the Gypsy peculation in France. Within GPIIIa, a 2 base-pair deletion in exon 6 was identified in patient LD and a deletion and premature termination in exon 3 caused by a splice site mutation was identified in patient Amsterdam l. ... 

Hutton M, Lendon CL, Rizzu P, Baker M, Froehch S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Heutink P (1998) Association of missense and 5 -splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393 702-705. 

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