Gene defect

The gene defective in cystic fibrosis codes for CFTR (cystic fibrosis transmembrane condnctance regulator), a membrane protein that pumps CP out of cells. If this CP pump is defective, CP ions remain in cells, which then take up water from the surrounding mucus by osmosis. The mucus thickens and accumulates in various organs, including the lungs, where its presence favors infections such as pneumonia. Left untreated, children with cystic fibrosis seldom survive past the age of 5 years. 

Transgenic animal models with spontaneous or induced receptor gene defects have been instrumental in elucidating the physiological roles of the LDL receptor gene family. In addition, a number of human diseases have been identified that are caused by sporadic or inherited forms of receptor deficiency (Table 1). 

Sialin was first identified as the product of the gene defective in sialidosis, a lysosomal storage disorder. The transporter mediates the movement of sialic acid out of lysosomes by coupling to the proton electrochemical gradient across the lysosomal membrane. Unlike the vesicular neurotransmitter transporters which are antiporters, sialin is a sympoiter with sialic acid and protons both moving out of the lysosome. 

Familial hypercholesterolaemia is characterized by a significant elevation in plasma LDL concentration. The basic metabolic defect appears to be abnormal LDL receptor function, arising from mutations in the LDL receptor gene. Several receptor mutations have been identified and hypercholesterolaemia severity as well as the age of onset of ischaemic heart disease has recently been demonstrated to vary according to the type of LDL receptor gene defect (Moorjani et al., 1993). 

Reitsma P. H. Protein C deficiency From gene defects to disease. Thromb Haemost 1997 78, 344-50. 

Alex Rosenberg John, do you think that some forms of mental retardation are caused by the single-gene defect that leads to fatal PKU ... 

Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastroenterology 2001 120(6) 1459—1467. 

The function of the ALD protein is not fully understood, and knockout mice lacking it do not exhibit the severe CNS neurological deficits commonly associated with the human disease despite a similar accumulation of VLCFAs [26], Furthermore, the clinical variability in human patients cannot be accounted for by the severity of the biochemical abnormality or the nature of the gene defect. These observations, plus other data from mice with defects in VLCFA metabolism, raise the issue of whether the accumulation of VLCFAs in myelin is crucial to the pathological mechanisms or is an epiphenomenon. Unlike most other lipid-storage diseases, active ALD brain lesions are characterized by perivascular accumulation of lymphocytes. For this reason, it has been hypothesized that the severity of CNS pathology may relate to an autoimmune reaction that varies from patient to patient and... 

Table 41-4 shows that nine of the 12 Zellweger spectrum disorders show a considerable range of severity of clinical manifestations. Clinical and biochemical studies do not correlate with the type of gene defect. There is, however, considerable correlation between the severity of clinical manifestations and the degree to which a specific mutation compromises import function in vitro. For example in PEX1 deficiency, 75% of patients with the G843D allele, in which import is 15% retained, had the relatively mild IRD phenotype, compared to those with the C.2097insT, which abolishes import completely, where only 13% had the IRD phenotype. Such correlations also exist in patients with the PEX 7 defect [ 10]. 

On the one hand, the biochemical study of the neuro-pathological lesions led to the identification of their main molecular components. On the other hand, the study of rare, familial forms of Alzheimer s disease, frontotemporal dementia and Parkinson s disease led to the identification of gene defects that cause inherited variants of the different diseases. Remarkably, in these cases, the defective genes have been found to encode or increase the expression of the main components of the neuropathological lesions. It has therefore been established that the basis of the familial forms of these diseases is a toxic property conferred by mutations in the proteins that make up the filamentous lesions. A corollary of this insight is that a similar toxic property may also underlie the much more common, sporadic forms of the diseases. 

Huntington s disease is a disease with a known and testable gene defect, which produces symptoms late in life. This constellation of clinical features makes this disorder... 

Collinge, J. et al. Presymptomatic detection or exclusion of prion protein gene defects in families with inherited prion diseases. Am. J. Hum. Genet. 49 1351-1354,1991. 

SCIDGeneTherapy Trial Infantswithsevere combined immunodeficiency disease (SCID, bubble boy syndrome) have a gene defect that leads to a complete lack of white blood cells. Without treatment, these infants die from comphcations of infectious diseases during the first few years of life. The only treatment currently approved for this condition is a bone marrow transplant. 

Answer B, Inheritance only from affected females strongly suggests a defect in a mitochondrial gene. Defects in mitochondrial gene expression phenotypkaUy present as problems in nerves and/or muscles, tissues with high aerobic metabolism. 

TABLE 1. Mutant human and mammalian cells with TK and GPRT gene defects (after S. M. Tugizov, 1996)... 

Genetic inactivation of pRb is observed in many tumors. The gene defect may affect the promoter region of the pRb gene, leading to reduced pRb expression, or it may... 

Kass S, McRae C, Graber HL, Sparks EA, McNamara D, Boudoulas H, Basson CT, Baker PB 3rd, Cody RJ, Fishman MC, Cox N, Kong A, Wooley CF, Seidman JG, Seidman CE A gene defect that causes conduction system disease and dilated cardiomyopathy maps to chromosome lpl-lql. Nat Genet 1994 7 546-551. 

TALDO deficiency can be confirmed in lymphoblasts, fibroblasts and in erythrocytes. These cells are incubated with ribose-5-phosphate, after which formation of transketolase and TALDO products are analysed by gas chromatography with nitrogen phosphorous detection by liquid chromatography tandem mass spectrometry [8, 11]. A similar enzyme assay is available for RPI [2]. Confirmation of the gene defect can be performed by sequence analysis. Disease-causing mutations have been detected in all TALDO-deficient patients and in the RPI-deficient patient. 

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