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Z Farfel

Publications and source records attributed to Z Farfel.

At least 19 recordsLinked to original sources
PubMed1998

G-protein diseases furnish a model for the turn-on switch.

How does a trimeric G protein on the inside of a cell membrane respond to activation by a transmembrane receptor? G-protein mutations in patients with hypertension and inherited endocrine disorders enhance or block signals from stimulated receptors. In combination with three-dimensional crystal structures and results from biochemical experiments, the phenotypes produced by these mutations suggest a model for the molecular activation mechanism that relays hormonal and sensory signals transmitted by many transmembrane receptors.

GTP-Binding Proteins↗
PubMed1997

Conditional activation defect of a human Gsalpha mutant.

Hormonal signals activate trimeric G proteins by promoting exchange of GTP for GDP bound to the G protein's alpha subunit (Galpha). Here we describe a point mutation that impairs this activation mechanism in the alpha subunit of Gs, producing an inherited disorder of hormone responsiveness. Biochemical analysis reveals an activation defect that is paradoxically intensified by hormonal and other stimuli. By substituting histidine for a conserved arginine residue, the mutation removes an internal salt bridge (to a conserved glutamate) that normally acts as an intramolecular hasp to maintain tight binding of the gamma-phosphate of GTP. In its basal, unperturbed state, the mutant alphas binds guanosine 5'-[gamma-thio]triphosphate (GTP[gammaS]), a GTP analog, slightly less tightly than does normal alphas, but (in the GTP[gammaS]-bound form) can stimulate adenylyl cyclase. The activation defect becomes prominent only under conditions that destabilize binding of guanine nucleotide (receptor stimulation) or impair the ability of alphas to bind the gamma-phosphate of GTP (cholera toxin, AlF4- ion). Although GDP release is usually the rate-limiting step in nucleotide exchange, the biochemical phenotype of this mutant alphas indicates that efficient G protein activation by receptors and other stimuli depends on the ability of Galpha to clasp tightly the GTP molecule that enters the binding site.

Adenylyl Cyclases↗
PubMed1997

Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21.

Essential hypertension is a common multifactorial trait. The molecular basis of a number of rare diseases that after blood pressure in humans has been established, identifying pathways that may be involved in more common forms of hypertension. Pseudohypoaldosteronism type II (PHAII, also known as familial hyperkalaemia and hypertension or Gordon's syndrome; OMIM #145260), is characterized by hyperkalaemia despite normal renal glomerular filtration, hypertension and correction of physiologic abnormalities by thiazide diuretics. Mild hyperchloremia, metabolic acidosis and suppressed plasma renin activity are variable associated findings. The pathogenesis of PHAII is unknown, although clinical studies indicate an abnormality in renal ion transport. As thiazide diuretics are among the most efficacious agents in the treatment of essential hypertension, understanding the pathogenesis of PHAII may be of relevance to more common forms of hypertension. Analysis of linkage in eight PHAII families showing autosomal dominant transmission demonstrates locus heterogeneity of this trait, with a multilocus lod score of 8.1 for linkage of PHAII to chromosomes 1q31-q42 and 17p11-q21. Interestingly, the chromosome-17 locus overlaps a syntenic interval in rat that contains a blood pressure quantitative trait locus (QTL). Our findings provide a first step toward identification of the molecular basis of PHAII.

Animals↗
PubMed1997

Effect of venous obstruction of lower extremities on exercise tolerance.

The effect of venous obstruction on effort tolerance is not well appreciated. We studied a patient with severe lower body venous obstruction (with near normal heart and lung function) who had marked exercise intolerance. Peak O2 uptake for leg exercise was reduced, but peak O2 uptake for upper extremities was normal. This difference indicates that severe venous obstruction can lead to exercise limitation.

Arm↗
PubMed1996

Pseudohypoparathyroidism, a novel mutation in the betagamma-contact region of Gsalpha impairs receptor stimulation.

Pseudohypoparathyroidism, type Ia (PHP-Ia), is a dominantly inherited endocrine disorder characterized by resistance to hormones that act by stimulating adenylyl cyclase. It is caused by inheritance of an autosomal mutation that inactivates the alpha subunit (alphas) of Gs, the stimulatory regulator of adenylyl cyclase. In three members of a family, the PHP-Ia phenotype is associated with a mutation (R231H) that substitutes histidine for an arginine at position 231 in alphas. We assessed signaling function of alphas-WT versus alphas-R231H transiently transfected in HEK293 cells. Hormone receptor-dependent stimulation of cAMP accumulation in cells expressing alphas-R231H is reduced by approximately 75% in comparison to cAMP accumulation in cells expressing alphas-WT. A second mutation, alphas-R201C, inhibits the GTPase turnoff reaction of alphas, thus producing receptor-independent stimulation of cAMP accumulation. The double mutant, alphas-R231H/R201C, stimulates cAMP accumulation almost as well (approximately 80%) as does alphas-R201C itself, indicating that the R231H mutation selectively impairs receptor-dependent signaling. In three-dimensional structures of G protein heterotrimers, Arg-231 is located in a region, switch 2, that is thought to interact with the betagamma subunit rather than with the hormone receptor. Thus, the R231H phenotype suggests that switch 2 (perhaps in concert with betagamma) mediates G protein activation by receptors at a site distant from the receptor-G protein contact surface.

Adenylyl Cyclases↗
PubMed1996

Pseudohypoparathyroidism type Ia: two new heterozygous frameshift mutations in exons 5 and 10 of the Gs alpha gene.

Pseudohypoparathyroidism type Ia (PHP-Ia) is a hereditary disease characterized by resistance to PTH and other hormones that act via cAMP. Patients have deficient activity of Gs alpha, the alpha subunit of the G protein, which couples hormone receptors to stimulation of adenylate cyclase. We describe two new mutations discovered in two sporadic patients with PHP-Ia. Using genomic DNA, we have amplified exons 2-13 of the Gs alpha gene (GNAS1) by PCR, and sequenced the resulting products. Both patients had Albright's hereditary osteodystrophy, resistance to multiple hormones, and deficient Gs alpha activity. In the first patient, a deletion of a C in exon 5 at codon 115 was found. In the second patient, an insertion of a C in exon 10 at codon 267 was detected. Both these heterozygous mutations cause frameshift, and predict decreased production of Gs alpha. This report adds two new Gs alpha mutations to the known ten mutations recently described.

Adolescent↗
PubMed1996

Familial Albright's hereditary osteodystrophy with hypoparathyroidism: normal structural Gs alpha gene.

Albright's hereditary osteodystrophy (AHO) is a characteristic skeletal phenotype, including short stature, obesity, round face, and brachydactyly. AHO appears in patients with pseudohypoparathyroidism (PHP) who have resistance to PTH and in their eumetabolic family members who have pseudopseudohypoparathyroidism (PPHP). The differential diagnosis of AHO in families without PHP includes brachydactyly E, whose existence as a distinct entity has been questioned. We studied a patient with familial AHO who presented with hypocalcemia. To our surprise, PTH levels were low, and the response to PTH administration was normal. This is the first case of familial AHO with hypoparathyroidism. The proband's family included 22 affected subjects spanning 3 generations, who had variable degrees of AHO manifestations, with an autosomal dominant inheritance trait. The metacarpophalangeal pattern profile was typical of that of PHP-PPHP. As deficient activity and inactivating mutations of Gs alpha were described in PHP as well as in PPHP, we measured the biological activity of Gs in family members, which was normal. To exclude subtle abnormalities in the Gs alpha gene, we sequenced the entire coding region of Gs alpha in the propositus, which was normal. We conclude that hypocalcemia should be adequately evaluated even in the presence of familial AHO, and that familial AHO can occur with a normal coding structural Gs alpha gene. Identification of the molecular defect in familial AHO without PHP will shed light on the pathogenesis of AHO in general.

Adult↗
PubMed1996

Carboxyl-terminal mutations of Gq alpha and Gs alpha that alter the fidelity of receptor activation.

The carboxyl terminus of the G protein alpha subunit is a key determinant of the fidelity of receptor activation. We have previously shown that the Gq alpha subunit (alpha q) can be made to respond to alpha i-coupled receptors by replacing its carboxyl terminus with the corresponding alpha i2, alpha o, alpha z residues. We now extend these findings in three ways: 1) carboxyl-terminal mutations of alpha q/alpha i chimeras show that the critical amino acids are in the -3 and -4 positions, 2) exchange of carboxyl termini between alpha q and alpha z allows activation by receptors appropriate to the carboxyl-terminal residues, and 3) we identify receptors that either do or do not activate the expected carboxyl-terminal chimeras (alpha q/alpha i, alpha q/alpha s, alpha s/alpha q). Replacement of the five carboxyl-terminal amino acids of alpha q with the alpha s sequence permitted an alpha s-coupled receptor (the V2 vasopressin receptor but not the beta 2-adrenergic receptor) to stimulate phospholipase C. Replacement of the five carboxyl-terminal amino acids of alpha z with residues of alpha q permitted certain alpha q-coupled receptors (bombesin and V1a vasopressin receptors but not the oxytocin receptor) to stimulate adenylyl cyclase. Thus, the relative importance of the G alpha carboxyl terminus in permitting coupling to a new receptor depends on the receptor with which it is paired. These studies refine our understanding and provide new tools with which to study the fidelity of receptor/G alpha activation.

Animals↗
PubMed1996

Multiple spurious laboratory results in a patient with hyperlipemic pancreatitis treated by plasmapheresis.

Hyperlipidemia is a known cause for acute pancreatitis. Hyperlipidemia may also produce multiple spurious laboratory results that may complicate the diagnosis and management of pancreatitis. We encountered such a patient who had the following spurious laboratory results: normal serum amylase activity, hyponatremia, and high hemoglobin levels. These laboratory artifacts were previously described, mostly separately. In addition, our patient had artifactual thrombocytopenia. The patient improved dramatically following plasmapheresis, which enhanced reduction of serum lipids.

Acute Disease↗
PubMed1995

Prolonged therapy by the combination of furosemide and thiazides in refractory heart failure and other fluid retaining conditions.

The efficacy and side effects of the combination therapy of thiazide and furosemide administered to patients with refractory heart failure, for a prolonged period of time, were assessed. Thirty-two patients were hospitalized during the years 1985-1991. Left heart failure (left ventricular ejection fraction (LVEF = 22.4% +/- 6.6%) was present in 26 patients, right heart failure in 3 patients, chronic renal failure, cirrhosis and bilateral pleural effusion were present each in one patient. Chlorothiazide 0.5 g daily was added to conventional therapy. Patients were monitored closely during hospitalization and later as outpatients. During hospitalization, addition of chlorothiazide caused a reduction of 4.8 +/- 4.0 kg in patients' weight, serum potassium decreased from 4.4 +/- 0.6 to 4.0 +/- 0.5 mmol/l (P < 0.005) and serum sodium from 139.0 +/- 4.7 to 136.8 +/- 5.5 mmol/l (P < 0.05). The duration of the combined therapy was 17.2 +/- 19.1 months. Thirteen patients had short treatment (1.6 +/- 0.8 months) and 19 patients had prolonged treatment (26.5 +/- 19.0 months). No specific characteristics distinguished patients in both groups. Thiazides were discontinued in 19 patients, 10 of which had side effects. In only 5 of the 19 patients treated for the prolonged period had thiazides to be discontinued because of side effects. Addition of thiazides to furosemide is efficacious in severe heart failure. The combination should be started during hospitalization. Many patients can be maintained on this combination for a prolonged period of time on an ambulatory basis.

Aged↗
PubMed1995

[Oculopharyngeal muscular dystrophy with dysphagia in a Jewess from Uzbekistan].

An 82-year-old Jewish woman from Tashkent, Uzbekistan was hospitalized because of dysphagia and weight loss. Physical examination revealed bilateral ptosis. The diagnosis of the rare inherited disease oculopharyngeal muscular dystrophy was confirmed by electron microscopy of biopsied muscle. It has recently been found that the prevalence of the disease among Jews from Uzbekistan is very high. It should therefore be considered when such patients present with dysphagia, so invasive imaging procedures can be avoided.

Aged↗