1/38. Novel mutation of the P0 extracellular domain causes a Dejerine-Sottas syndrome.A patient is described with a Dejerine-Sottas syndrome caused by a novel heterozygous Cys(98)Tyr mutation in the extracellular domain of the major peripheral myelin protein zero (P0ex). Homotypical interactions between P0ex tetramers of apposed extracellular faces of the Schwann cell membrane play a crucial part in myelin compaction. The amino acid change disrupts a unique disulphide bond that stabilises the immunoglobulin-like structure of P0ex and it is predicted to cause severe dehypomyelination through dominant negative effects on the wild type protein.- - - - - - - - - - ranking = 1keywords = wild (Clic here for more details about this article) |
2/38. Short stature by mutant growth hormones.Although the presence of a short stature caused by biologically inactive growth hormone (GH) has been presumed by many case reports, its molecular basis has been unclear until recently. Short stature with low concentrations of insulin-like growth factor-I (IGF-I), despite normal to high GH concentration, suggests impaired GH effect. Recently, we have reported two unique point mutations in the GH1 gene in short children whose GH was thought to be bioinactive. The mutant GH, D112G, was found to lose the capability to transduce GH-dependent signals by impaired dimerization of GH receptors. This case was the first example that proved the molecular mechanism of bioinactive GH syndrome. Another mutant GH, R77C, was so unique that it failed to stimulate GH-induced tyrosine phosphorylation in the cells by itself, but also inhibited the activity of wild-type GH, indicating an antagonistic effect of this mutant GH. The severity of short stature and the responses to exogenous GH were different in these cases. It was supposed that the molecular heterogeneity of mutant GH reflected clinical phenotypes of bioinactive GH syndrome.- - - - - - - - - - ranking = 1keywords = wild (Clic here for more details about this article) |
3/38. A new mutation (G51C) in the iron-responsive element (IRE) of L-ferritin associated with hyperferritinaemia-cataract syndrome decreases the binding affinity of the mutated IRE for iron-regulatory proteins.Hereditary hyperferritinaemia-cataract syndrome is an autosomal dominant disorder characterized by a constitutively increased synthesis of L-ferritin in the absence of iron overload. The disorder is associated with point mutations in the iron-responsive element (IRE) of L-ferritin mRNA. We report a new mutation, G51C, identified in two members of a Canadian family, presenting a moderate increase in serum ferritin and a clinically silent bilateral cataract. Gel retardation assays showed that the binding of the mutated IRE to iron-regulatory proteins (IRPs) was reduced compared with the wild type. Structural modelling predicted that the G51C induces a rearrangement of base pairing at the lateral bulge of the IRE structure which is likely to modify IRE conformation.- - - - - - - - - - ranking = 1keywords = wild (Clic here for more details about this article) |
4/38. Characterization of a novel mitochondrial dna deletion in a patient with a variant of the Pearson marrow-pancreas syndrome.We have recently diagnosed a patient with anaemia, severe tubulopathy, and diabetes mellitus. As the clinical characteristics resembled Pearson marrow-pancreas syndrome, despite the absence of malfunctioning of the exocrine pancreas in this patient, we have performed dna analysis to seek for deletions in mtDNA. dna analysis showed a novel heteroplasmic deletion in mtDNA of 8034bp in length, with high proportions of deleted mtDNA in leukocytes, liver, kidney, and muscle. No deletion could be detected in mtDNA of leukocytes from her mother and young brother, indicating the sporadic occurrence of this deletion. During culture, skin fibroblasts exhibited a rapid decrease of heteroplasmy indicating a selection against the deletion in proliferating cells. We estimate that per cell division heteroplasmy levels decrease by 0.8%. By techniques of fluorescent in situ hybridisation (FISH) and mitochondria-mediated transformation of rho(o) cells we could show inter- as well as intracellular variation in the distribution of deleted mtDNA in a cell population of cultured skin fibroblasts. Furthermore, we studied the mitochondrial translation capacity in cybrid cells containing various proportions of deleted mtDNA. This result revealed a sharp threshold, around 80%, in the proportion of deleted mtDNA, above which there was strong depression of overall mitochondrial translation, and below which there was complementation of the deleted mtDNA by the wild-type dna. Moreover, catastrophic loss of mtDNA occurred in cybrid cells containing 80% deleted mtDNA.- - - - - - - - - - ranking = 1keywords = wild (Clic here for more details about this article) |
5/38. Genetic analysis of two female patients with incomplete denys-drash syndrome.denys-drash syndrome (DDS) is characterized by genital anomaly, early onset nephropathy and high risk for developing Wilms' tumor (WT). Recently, mutations in exon 8 or 9 of the Wilms' tumor suppressor gene (WT1) have been found in the majority of DDS patients studied. We analyzed these two exons of the WT1 gene in genomic dna from two female patients with DDS by using polymerase-chain reaction (PCR) and direct sequencing. The patients were accompanied with normal external genitalia, early onset renal failure between 6 and 12 months of age, and unilateral Wilms' tumor. Genomic dna was isolated from peripheral blood leucocytes of the patients. Amplification of exons 8 and 9 of the WT1 gene by PCR was performed, and direct sequencing of the PCR product was performed using an automatic dna sequencer. Two heterozygous missense mutations were found in these patients, including a missense mutation in exon 9 at codon 388 replacing the wild-type Cys with Phe, and a previously described mutation in exon 9 at codon 398 replacing the wild-type Leu with Pro. Cys388Phe is a novel mutation in the WT1 gene in the DDS. These cases are considered to be "incomplete DDS" with nephropathy and Wilms' tumor and without genital anomaly, the validity of which has been confirmed by mutation analysis.- - - - - - - - - - ranking = 2keywords = wild (Clic here for more details about this article) |
6/38. Identification of a dominant negative homeodomain mutation in Rieger syndrome.Mutations in the PITX2 bicoid-like homeobox gene cause Rieger syndrome. Rieger syndrome is an autosomal-dominant human disorder characterized by glaucoma as well as dental hypoplasia, mild craniofacial dysmorphism, and umbilical stump abnormalities. PITX2 has also been implicated in the development of multiple organs and left-right asymmetry in the body plan. The PITX2 homeodomain has a lysine at position 50, which has been shown to impart the bicoid-type (TAATCC) dna binding specificity to other homeodomain proteins. A mutation (K88E), found in a Rieger syndrome patient, changes this lysine to glutamic acid. We were intrigued by the relatively pronounced phenotypic consequences of this K88E mutation. In the initial analyses, the mutant protein appeared to simply be inactive, with essentially no dna binding and transactivation activities and, unlike the wild type protein, with an inability to synergize with another transcription factor, Pit-1. However, when the K88E dna was cotransfected with wild type PITX2, analogous to the patient genotype, the K88E mutant suppressed the synergism of wild type PITX2 with Pit-1. In contrast, a different PITX2 homeodomain mutant, T68P, which is also defective in dna binding, transactivation, and Pit-1 synergism activities, did not suppress the wild type synergism with Pit-1. These results describe the first dominant negative missense mutation in a homeodomain and support a model that may partially explain the phenotypic variation within Rieger syndrome.- - - - - - - - - - ranking = 4keywords = wild (Clic here for more details about this article) |
7/38. Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice.Three genes, TTF1, TTF2, and PAX8, involved in thyroid gland development and migration have been identified. Yet systematic screening for defects in these genes in thyroid dysgenesis gave essentially negative results. In particular, no TTF1 gene defects were found in 76 individuals with thyroid dysgenesis even though a deletion of this gene in the mouse results in thyroid and lung agenesis and defective diencephalon. We report a 6-year-old boy with predominant dyskinesia, neonatal respiratory distress, and mild hyperthyrotropinemia. One allele of his TTF1 gene had a guanidine inserted into codon 86 producing a nonsense protein of 407, rather than 371, amino acids. The mutant TTF1 did not bind to its canonical cis-element or transactivate a reporter gene driven by the thyroglobulin promoter, a natural target of TTF1. Failure of the mutant TTF1 to interfere with binding and transactivation functions of the wild-type TTF1 suggested that the syndrome was caused by haploinsufficiency. This was confirmed in mice heterozygous for Ttf1 gene deletion, heretofore considered to be normal. Compared with wild-type littermates, Ttf1( /-) mice had poor coordination and a significant elevation of serum thyrotropin. Therefore, haploinsufficiency of the TTF1 gene results in a predominantly neurological phenotype and secondary hyperthyrotropinemia.- - - - - - - - - - ranking = 2keywords = wild (Clic here for more details about this article) |
8/38. EEC (Ectrodactyly, ectodermal dysplasia, Clefting) syndrome: heterozygous mutation in the p63 gene (R279H) and dna-based prenatal diagnosis.BACKGROUND: Germline mis-sense mutations in the dna-binding domain of the p63 gene have recently been established as the molecular basis for the autosomal dominant EEC (Ectrodactyly, ectodermal dysplasia, Clefting) syndrome. OBJECTIVES: To examine genomic dna from a 36-year-old woman, her 58-year-old father and her 11-year-old son, all with the EEC syndrome, to determine the inherent p63 mutation and, after genetic counselling, to use knowledge of the mutation to undertake a first-trimester dna-based prenatal diagnosis in a subsequent pregnancy. methods: Fetal dna was extracted from chorionic villi and used to amplify exon 7 of p63 containing the potential mutation. Direct sequencing and restriction endonuclease digestion (loss of AciI site on mutant allele) were used for dna-based prenatal diagnosis. RESULTS: We identified a heterozygous arginine to histidine p63 mutation, R279H, in all three affected individuals. prenatal diagnosis demonstrated a homozygous wild-type sequence predicting an unaffected child: a healthy boy was subsequently born at full-term. CONCLUSIONS: These data expand the p63 gene mutation database and provide the first example of a dna-based prenatal test in this ectodermal dysplasia syndrome.- - - - - - - - - - ranking = 1keywords = wild (Clic here for more details about this article) |
9/38. A novel mutation in the FOXL2 gene in a patient with blepharophimosis syndrome: differential role of the polyalanine tract in the development of the ovary and the eyelid.blepharophimosis/ptosis/epicanthus inversus syndrome (BPES) is an autosomal dominant disorder characterized by abnormalities of the eyelids. We herein report a 12-year-old girl with BPES who had bilateral blepharophimosis, ptosis, hypertelorism, and downslanting palpebral fissures. mutation analysis revealed the insertion of a cytosine (dup 1036C) within a wild-type run of six cytosines. A comparison of the phenotypic outcomes of the previously described mutations and the dup 1036C mutation reported herein suggest that the outcome is largely dependent on the involvement of the polyalanine tract (residues 221 to 231). We suggest that the polyalanine tract may have a differential role in eyelid and ovarian development and function. Further work is required to clarify whether ovarian function can be predicted on the basis of genotype.- - - - - - - - - - ranking = 1keywords = wild (Clic here for more details about this article) |
10/38. Novel KCNJ2 mutation in familial periodic paralysis with ventricular dysrhythmia.BACKGROUND: Mutations in the KCNJ2 gene, which codes cardiac and skeletal inward rectifying K channels (Kir2.1), produce Andersen's syndrome, which is characterized by periodic paralysis, cardiac arrhythmia, and dysmorphic features. methods AND RESULTS: In 3 Japanese family members with periodic paralysis, ventricular arrhythmias, and marked QT prolongation, polymerase chain reaction/single-strand conformation polymorphism/dna sequencing identified a novel, heterozygous, missense mutation in KCNJ2, Thr192Ala (T192A), which was located in the putative cytoplasmic chain after the second transmembrane region M2. Using the xenopus oocyte expression system, we found that the T192A mutant was nonfunctional in the homomeric condition. Coinjection with the wild-type gene reduced the current amplitude, showing a weak dominant-negative effect. CONCLUSIONS: T192, which is located in the phosphatidylinositol-4,5-bisphosphate binding site and also the region necessary for Kir2.1 multimerization, is a highly conserved amino acid residue among inward-rectifier channels. We suggest that the T192A mutation resulted in the observed electrical phenotype.- - - - - - - - - - ranking = 1keywords = wild (Clic here for more details about this article) |
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