The human phenotype with primarily impaired myelination is represented by hypomyelinating leukodystrophies. The most frequent form is Pelizaeus-Merzbacher disease, which is due to alterations in the PLP1 gene encoding the major myelin protein. Another form, Pelizaeus-Merzbacher-like disease, is partly associated with mutations in the GJA12 gene encoding gap junction protein ...

Mutations in the COL1A1 and COL1A2 genes, encoding the proalpha1 and 2 chains of type I collagen, cause osteogenesis imperfecta (OI) or Ehlers-Danlos syndrome (EDS) arthrochalasis type. Although the majority of missense mutations in the collagen type I triple helix affect glycine residues in the Gly-Xaa-Yaa repeat, few nonglycine substitutions ...

A PARK8 form of Parkinson's disease (PD) is caused by a novel gene, leucine-rich repeat kinase 2 (LRRK2), and a single mutation G2019S was found in a proportion of LRRK2-associated cases of diverse ethnic origins. We performed the LRRK2 G2019S mutation analysis in 304 Russian patients with PD, including 291 ...

Early onset of vestibular schwannoma (VS) is associated with the inherited condition neurofibromatosis type 2 (NF2). However, the majority of NF2 presents bilaterally and the proportion of early-onset apparent sporadic unilateral VS because of NF2 remains to be determined. We have determined the risk by studying NF2 risk in a ...

We report a novel mutation detected in a 33 year old Chinese man with congenital bilateral absence of the vas deferens (CBAVD), a past history of pulmonary meliodosis infection and a past history of bronchiolitis obliterans organising pneumonia. A novel splice site mutation in intron 6b (1001+5 G-->A) in the ...

Plasmodium vivax is a serious health concern in many regions and is sometimes inadvertently treated with sulfadoxine-pyrimethamine (SP). Mutations in the genes that encode dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) confer resistance to pyrimethamine and sulfadoxine, respectively. Numerous studies have examined the prevalence and diversity of mutations in P. ...

OBJECTIVE: To investigate possible genotype-phenotype correlations and to evaluate the natural history of patients with Charcot-Marie-Tooth disease type 1X (CMT1X). BACKGROUND: CMT1X is caused by over 260 distinct mutations in the gap junction beta 1 (GJB1) gene, located on the X chromosome, which encodes the gap junction protein connexin 32 ...

Homozygosity or compound heterozygosity for the c.833T>C transition (p.I278 T) in the cystathionine beta-synthase (CBS) gene represents the most common cause of pyridoxine-responsive homocystinuria in Western Eurasians. However, the frequency of the pathogenic c.833C allele, as observed in healthy newborns from several European countries (q(c.833C) approximately equals 3.3 x 10(-3)), ...

Although denaturing gradient gel electrophoresis (DGGE) is a highly effective technique for screening for TP53 mutations, the use of denaturing high performance liquid chromatography (DHPLC) is a growing methodology. This report describes a comparison between DHPLC and DGGE in the detection of TP53 mutations in hematopoietic cell lines and lymphomas. ...

Most of the thousands of grapevine cultivars (Vitis vinifera L.) can be divided into two groups, red and white, based on the presence or absence of anthocyanin in the berry skin, which has been found from genetic experiments to be controlled by a single locus. A regulatory gene, VvMYBA1, which ...

Homozygosity for a novel hemochromatosis (HFE) gene splice site mutation (IVS5+1 G/A) was previously reported in a 48-year-old Vietnamese man residing in Germany who had an elevated serum ferritin (SF) and transferrin saturation (TS) and severe iron overload on liver biopsy. This mutation was not found in 222 controls of ...

Autosomal dominant OPK and BOS feature widespread foci of osteosclerotic trabeculae without or with skin lesions, respectively. Occasionally, a larger area of dense bone in OPK or BOS resembles MEL, a sporadic sclerosing disorder primarily involving cortical bone. Others, finding deactivating germline LEMD3 mutations in OPK or BOS, concluded such ...

Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphism, growth and mental retardation, microcephaly, and various malformations. Heterozygous mutations in the NIPBL gene have been detected in approximately 45% of affected individuals. Recently, a second CdLS gene, mapping to the X chromosome, has been identified: ...

Atypical megakaryocytes provide the histomorphological hallmark of all Philadelphia-chromosome negative chronic myeloproliferative disorder (Ph(-) CMPD) subtypes and have not been studied so far for the JAK2(V617F) mutation. The mutant gene dosage was determined in isolated megakaryocytes from 68 cases of JAK2(+)/Ph(-) CMPD by a pyrosequencing assay. Megakaryocytes from essential thrombocythemia ...

Vanishing white matter (VWM) is a childhood leukoencephalopathy with central hypomyelination, white matter rarefaction, and cystic degeneration. Adult onset, variable phenotype, and high frequency characterize Arg113His mutation caused by G338A polymorphism associated with VWM. A patient with trauma-associated onset, and clinical features compatible with multiple sclerosis (MS), was homozygous for ...

In Neurospora, the circadian rhythm is expressed as rhythmic conidiation driven by a feedback loop involving the protein products of frq (frequency), wc-1 (white collar-1), and wc-2, known as the frq/wc (FWC) oscillator. Although strains carrying null mutations such as frq(10) or wc-2Delta lack a functional FWC oscillator and do ...

Mutations in the cohesin regulators NIPBL and ESCO2 are causative of the Cornelia de Lange syndrome (CdLS) and Roberts or SC phocomelia syndrome, respectively. Recently, mutations in the cohesin complex structural component SMC1A have been identified in two probands with features of CdLS. Here, we report the identification of a ...

INTRODUCTION: Malignant paragangliomas have been well described in carriers of mutations of the succinate dehydrogenase B (SDHB) gene, but have rarely been associated with mutations in the succinate dehydrogenase D (SDHD) gene. AIM: The aim of the study was to report the different clinical expression patterns of malignant paragangliomas in ...

OBJECTIVE: To assess the resistance profile of tipranavir. METHODS: Resistance analyses were performed on Boëhringer Ingelheim-sponsored studies examining the safety and efficacy of tipranavir in highly treatment-experienced individuals at 24 weeks. Virologic response rates based on the presence of baseline primary protease inhibitor mutations and based on baseline tipranavir susceptibility ...

The mouse seminal vesicle shape (svs) mutation is a spontaneous recessive mutation that causes branching morphogenesis defects in the prostate gland and seminal vesicles. Unlike many other mutations that reduce prostatic and/or seminal vesicle branching, the svs mutation dramatically reduces branching without reducing organ growth. Using a positional cloning approach, ...

We investigated the association between exposure to trichloroethylene (TCE) and mutations in the von Hippel-Lindau (VHL) gene and the subsequent risk for renal cell carcinoma (RCC). Cases were recruited from a case-control study previously carried out in France that suggested an association between exposures to high levels of TCE and ...

BACKGROUND: Cystic fibrosis (CF) mice, created with a genetically engineered mutation in the Cystic fibrosis transmembrane conductance regulator (Cftr) gene, may develop intestinal plugs which limit their survival past weaning. In a studied population of genetically mixed CF mice differences in allelic ratios at particular loci, between surviving CF mice ...

The intensity of flower colour, mainly determined by the amount of anthocyanin, is an important horticultural trait. To modulate flower colour intensity, post-transcriptional gene silencing (PTGS)-based technology has been widely used. The constraint of PTGS, however, is that it requires a high degree of conservation in the nucleotide sequences of ...

Lipoid proteinosis is caused by loss-of-function mutations in the glycoprotein extracellular matrix protein 1 (ECM1). We report here mutation analysis of the ECM1 gene in a Chinese family with lipoid proteinosis. A 10-year-old boy presented with a hoarse voice, acneiform scars and yellow skin nodules, as well as beaded eyelid ...

OBJECTIVE: An association between maternal HELLP syndrome and fetal long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency has been proposed. LCHAD catalyzes the third step in the beta-oxidation of fatty acids in mitochondria. Whereas about 75% of LCHAD-deficient patients carry a G-to-C mutation at nucleotide position 1528 (Glu474Gln, E474Q) on both chromosomes, ...

Ethylene oxide is a multisite carcinogen in rodents and classified as a human carcinogen by the National Toxicology Program. In 2-year mouse studies, ethylene oxide (EO) induced lung, Harderian gland (HG), and uterine neoplasms. We evaluated representative EO-induced and equivalent spontaneous neoplasms for K-ras mutations in codons 12, 13, and ...

Junctophilin subtypes, designated as JPH1 approximately 4, are protein components of junctional complexes and play essential roles in cellular Ca2+ signaling in excitable cells. Knockout mice lacking the cardiac-type Jph2 die of embryonic cardiac arrest, and the mutant cardiac myocytes exhibit impaired formation of peripheral couplings and arrhythmic Ca2+ signaling ...

We wished to investigate the effects of various mutations in HIV-1 reverse transcriptase (RT) on biochemical inhibition by the active form of a novel nucleoside termed apricitabine. Accordingly, we studied the efficiency of chain-termination mediated by apricitabine triphosphate (TP) in cell-free assays that used either recombinant wild-type or mutated RTs. ...

Patients with pyridoxine dependent epilepsy (PDE) present with early-onset seizures resistant to common anticonvulsants. According to the benefit of pyridoxine (vitamin B(6)) and recurrence of seizures on pyridoxine withdrawal, patients so far have been classified as having definite, probable, or possible PDE. Recently, PDE has been shown to be caused ...

In in vitro experiments, active transport of thyroid hormones had been repeatedly demonstrated. The membrane transporters for thyroid hormones which have been identified include the organic anion transporting polypeptide, heterodimeric amino acid transporters and the monocarboxylate transporters (MCT) which are the focus of this chapter. The gene encoding MCT8 which ...

Cellular uptake and release of thyroid hormone are mediated by transporters. Among these, monocarboxylate transporter 8 (MCT8) shows particularly high activity towards the active thyroid hormone 3,3',5-triiodothyronine (T(3)). MCT8 is expressed in different tissues, including the brain where it is predominantly localized in neurons. The MCT8 gene is located on ...

Few studies have investigated whether or not there is an interdependence between osmoregulation and vesicular trafficking. We previously showed that in Caenorhabditis elegans che-14 mutations affect osmoregulation, cuticle secretion, and sensory organ development. We report the identification of seven lethal mutations displaying che-14-like phenotypes, which define four new genes, rdy-1-rdy-4 ...

SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social ...

Costello syndrome (CS; MIM 218040) is characterized by short stature, facial dysmorphism, cardiac defects and predisposition to embryonal rhabdomyosarcoma (CS/ERMS) and other neoplasias. CS is caused by germline mutations in the HRAS gene on chromosome 11p15.5, a region showing allelic imbalances in sporadic ERMS and CS/ERMS. The critical gene for ...

Drosophila phototransduction serves as a model for phosphoinositide (PI) signaling and for characterizing the mechanisms regulating transient receptor potential (TRP) channels in vivo. Activation of TRP and TRP-like (TRPL) requires hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), resulting in the generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Although a role for ...

We previously identified in two families with early onset Parkinson's Disease (PD) from the isolated population of Antioquia (Colombia), a parkin Cys212Tyr substitution caused by a G736A mutation. This mutation was subsequently observed in a Spanish family, suggesting that it could have been taken to Antioquia by Spanish immigrants. Here ...

Mutations of G protein-coupled receptors are responsible for a wide range of diseases. With respect to water balance and vasopressin signaling, more than 180 different inactivating mutations have been previously described in the V2 vasopressin receptor (V2R), resulting in nephrogenic diabetes insipidus. In contrast, we have recently described the first ...

Combinatorial saturation mutagenesis -CSM- is a valuable tool for improving enzymatic properties from hot-spot residues discovered by directed enzyme evolution or performing semi-rational studies. CSM coupled to a reliable high-throughput screening assay -coefficient of variance below 10%- has been used to enhance turnover rates in the fungal laccase variant T2 ...

Mutations of Fog2 in mice result in a phenotype that includes pulmonary lobar defects. To determine whether formation of the accessory lobe bronchus is mediated by a Gata family cofactor, we evaluated embryonic lungs from mice carrying missense mutations that cause loss of FOG-GATA protein interaction. Lungs from embryos carrying ...

Familial hypomagnesemic hypercalciuria and nephrocalcinosis (FHHNC [MIM 248250]) is a rare renal tubular disorder characterized by impaired reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop (tALH), causing renal magnesium wasting and hypercalciuria. Patients with FHHNC usually present with recurrent urinary tract infections, polyuria, nephrolithiasis (NL) ...

Obstetrical complications such as preeclampsia, fetal growth restriction, and placental abruption are associated with inadequate placental perfusion. Previous studies have shown that the angiotensinogen (AGT) Thr235 mutation is associated with abnormal remodeling of the uterine spiral arteries and occurs at higher frequencies in preeclampsia. This study was done to evaluate ...

Trismus-pseudocamptodactyly syndrome (TPS) is a rare autosomal dominant distal arthrogryposis (DA) characterized by an inability to open the mouth fully (trismus) and an unusual camptodactyly of the fingers that is apparent only upon dorsiflexion of the wrist (i.e., pseudocamptodactyly). TPS is also known as Dutch-Kentucky syndrome because a Dutch founder ...

The revertant mutations G550E and 4RK [the simultaneous mutation of four arginine-framed tripeptides (AFTs): R29K, R516K, R555K, and R766K] rescue the cell surface expression and function of F508del-cystic fibrosis (CF) transmembrane conductance regulator (-CFTR), the most common CF mutation. Here, we investigate their mechanism of action by using biochemical and ...

The Raf/MEK/ERK (MAPK) signal transduction is an important mediator of a number of cellular fates including growth, proliferation, and survival. The BRAF gene is activated by oncogenic RAS, leading to cooperative effects in cells responding to growth factor signals. Our study was performed to elucidate a possible role of BRAF ...

The K70E mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) has become more prevalent in clinical samples, particularly in isolates derived from patients for whom triple-nucleoside regimens that include tenofovir (TNV), abacavir, and lamivudine (3TC) failed. To elucidate the molecular mechanism by which this mutation confers resistance ...

OBJECTIVE: To compare clinical features of CCM1, CCM2, and CCM3 mutation carriers. METHODS: A detailed clinical and molecular analysis of 163 consecutive cerebral cavernous malformation (CCM) families was performed. RESULTS: A deleterious mutation was detected in 128 probands. Three hundred thirty-three mutation carriers were identified (238 CCM1, 67 CCM2, and ...

A 30-year-old woman was found to have hyperferritinaemia after presenting with menorrhagia and lethargy. Serum iron studies did not confirm iron overload. Further investigations revealed two distinct genetic mutations of iron haemostasis--homozygosity for C282Y mutation of the HFE gene on chromosome 6 and heterozygosity for A40G mutation in the iron ...

Rubinstein-Taybi syndrome (RTS) is characterized by typical facies, short stature, mental retardation, broad thumbs and broad great toes. The syndrome is at least in part caused by microdeletions at chromosome 16p13.3 or by mutations in the gene for the CREB binding protein (CBP), which is located at 16p13.3. Familial Mediterranean ...

OBJECTIVE: Differences in iodine intake could account for the variable prevalences reported for somatic TSH receptor (TSHR) mutations in toxic thyroid nodules (TTNs). However, this question has not been settled, since no study has yet determined the TSHR mutation prevalence in regions with different iodine supplies in the same population ...

A single somatic mutation, V617F, in the pseudokinase domain of the Jak2 is the primary cause of many chronic myeloproliferative diseases. As valine 617 of Jak2 is conserved as valine 678 of Tyk2, we examined the effect of a homologous mutation in Tyk2 (V678F Tyk2) on cell growth. V678F Tyk2 ...