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PubMed1989

Gene dosage studies of a temperature sensitive Abruptex mutation of the Notch locus of Drosophila melanogaster.

Gene dosage studies of a temperature sensitive Abruptex mutation of the Notch locus of Drosophila melanogaster revealed, firstly, that hemizygous females were lethal at all temperatures studied, while hemizygous males were subvital at 18 degrees C, semilethal at 25 degrees C, and lethal at 29 degrees C. This is due to dosage compensation of the Notch locus. Secondly, it was observed that in general an increasing dose of the wild allele decreased the expression of Abruptex at all temperatures. An exception was the Axtsl/Axtsl/ + genotype, which was more expressed than Axtsl/Axtsl at low temperatures. This suggests antimorphism as the most likely mode of action of the temperature sensitive Abruptex mutation. Thirdly, it was observed that the expression of Abruptex phenotype increased from 18 degrees C to 25 degrees C but decreased from 25 degrees C to 29 degrees C if the wild type allele was involved in the genotype. This suggests that the gene product of the temperature sensitive Abruptex allele loses its function at high temperatures. The putative antimorphic mode of action of the temperature sensitive Abruptex mutation suggests that the Notch gene product interacts with products of other neurogenic loci or with itself.

Animals↗
PubMed1999

Molecular pathology of soft tissue and bone tumors. A review.

OBJECTIVE: To present recent concepts on the molecular pathogenesis of tumors of soft tissue and bone, and on the use of molecular genetic methods, including their significance as diagnostic markers and prognostic indicators. DATA SOURCES AND STUDY SELECTION: Reports on tumors of bone and/or soft tissue published in the English language literature and observations made using specimens available at the Departments of Pathology at Albany Medical College and Loyola University Medical Center. DATA EXTRACTION AND SYNTHESIS: Studies on bone and soft tissue tumors containing chromosomal or genetic evaluation were selected for further analysis. Specific chromosomal abnormalities, such as numerical aberrations or translocations with production of fusion genes, were classified according to the tumor of origin. Data were also collected on mutations in tumor suppressor genes, genes coding for growth factors or their receptors, and genes coding for tyrosine kinases. Also noted were mutations of uncertain significance, for which the pathogenic connection between tumor production and mutated gene function is still unclear. CONCLUSIONS: In general, the mutations reported interfere with the action of peptide growth factors coordinating mesenchyme proliferation and differentiation, although membrane-bound receptors expressing the intracellular signaling modifier, tyrosine kinase activity, have also been involved. Functional types of genes most commonly affected include tumor suppressors, oncogenes, and nuclear transcription factors. Thus, the mutations involved in the pathogenesis of soft tissue and bone tumors have affected multiple genes. Moreover, aberrant fusion gene products may be formed in tumoral tissue and may then act as transcription regulators stimulating cellular proliferation. Cytogenetic studies help at the clinical level by demonstrating aneuploidy and increased ploidy, which may correlate with malignant behavior. Diagnostic tumor-specific chromosomal translocations may be detected with Southern hybridization analysis, polymerase chain reaction, reverse-transcription polymerase chain reaction, or with the fluorescence in situ hybridization technique. Notably, early metastatic disease may be detectable in blood specimens using polymerase chain reaction or reverse-transcription polymerase chain reaction techniques.

Bone Neoplasms↗
PubMed1996

Resistance of human immunodeficiency virus type 1 to protease inhibitors: selection of resistance mutations in the presence and absence of the drug.

Inhibitors of the human immunodeficiency virus (HIV) protease are a promising class of antiviral agents that dramatically reduce HIV replication both in culture and in infected patients. However, as for many other antiviral compounds, long-term efficacy of these agents is impeded by the emergence of virus variants with increased resistance to their inhibitory action, following selection of specific mutations in the protease coding sequence. We have studied HIV-1 variants that emerged at different stages of selection in the presence of the C2-symmetrical protease inhibitor ABT-77003. The selection of variants was a gradual process during which mutations accumulated at different sites in the protease, generating virus populations with increasing levels of resistance to the drug. The initially selected viruses had a low level of resistance as well as a markedly reduced replicative capacity. Further accumulation of mutations at secondary sites led to an improvement in both drug resistance and replication. In spite of their reduced infectivity, partially selected virus populations did not readily revert to wild-type when serially passaged in drug-free conditions. Instead, even in the absence of drug, secondary mutations identical to those selected in the presence of the inhibitor continued to emerge. These mutations improved both the intrinsic replicative capacity of the virus and its level of resistance to the inhibitor, suggesting that once committed to drug resistance, readaptation of the enzyme to its natural substrate leads to a reduction of its sensitivity to the inhibitor.

Amino Acid Sequence↗
PubMed1992

Ion channels in action potential generation.

Molecular structure-function studies have identified the two key regions--the voltage sensor and pore--of the sodium and potassium channels responsible for the action potential in nerve axon. Mutational analysis has focused on the amino acids that are most important in each region. Similar studies in myocytes and nerve cell bodies are now being pursued.

Action Potentials↗
PubMed1999

Charcot-marie-tooth disease and related neuropathies: molecular basis for distinction and diagnosis.

Great advances have been made in understanding the molecular basis of Charcot-Marie-Tooth disease (CMT) and related neuropathies, namely Dejerine-Sottas disease (DSD), hereditary neuropathy with liability to pressure palsies (HNPP) and congenital hypomyelination (CH). The number of newly uncovered mutations and identified genetic loci is rapidly increasing, and, as a consequence, the classification of these disorders is becoming more complicated. Molecular genetics, animal models, and transfected cell studies are shedding light on function and dysfunction of proteins involved in hereditary myelinopathies-peripheral myelin protein 22 (PMP22), myelin protein zero (PO), connexin 32 (Cx32), and early growth response 2 (EGR2). Gene dosage effect, loss of function, gain of toxic function, and dominant negative effect are possible mechanisms whereby different gene mutations may exert their detrimental action on peripheral nerves. A tentative rational approach to clinical and molecular diagnosis based on genotype-phenotype correlation analysis is described.

Animals↗
PubMed1995

Gain-of-function mutations in a human calmodulin-like protein identify residues critical for calmodulin action in yeast.

A human epithelial cell-specific transcript (NB-1) encodes a calmodulin-like protein (hCLP), which is identical in length and 85% identical in amino acid sequence to authentic human calmodulin (hCaM). Although hCaM shares only 60% amino acid sequence identity with yeast calmodulin (CMD1 gene product), hCaM was able to substitute functionally for Cmd1 in yeast cells. In contrast, hCLP was unable to support either spore germination or vegetative growth in Cmd1-deficient yeast cells, even when stably expressed at a level at least an order of magnitude above that of hCaM. Thus, hCLP provides an indicator protein for discerning those residues that are critical for calmodulin function in vivo. In addition to 20 conservative amino acid replacements, hCLP differs from hCaM (and other vertebrate calmodulins that are able to complement a cmd1 null mutation) by only three nonconservative substitutions. Site-directed mutagenesis was used to convert these three positions back to residues more typical of those found in authentic calmodulins and to prepare all possible combinations of these three mutations, specifically: three single mutants (R58V, R112N, and A128E), three double mutants (R58V A128E, R112N A128E, and R58V R112N), and the triple mutant (R58V R112N A128E). The triple mutant and one of the double mutants (R58V A128E) were able to restore an apparently normal growth rate to a cmd1 delta strain, indicating that the altered hCLPs have acquired the ability to behave as functional calmodulins in yeast. The other two double mutants were able to support growth of Cmd1-deficient cells only weakly, but cells expressing the R112N A128E mutant grew noticeably better than those expressing the R58V R112N mutant. Remarkably, one single mutant (A128E), but not the other two single mutants, was also reproducibly able to support weak growth of a cmd1 delta strain. The properties of these gain-of-function, or neomorphic, mutations implicate E128, and to a lesser extent V58, as residues critical for calmodulin action in vivo. Molecular modeling of these positions within the structure of a Ca(2+)-calmodulin.peptide complex indicates that E128 projects directly into the central cavity occupied by the bound peptide. Thus, E128 may contribute a contact that is vital for the interaction of Cmd1 with one or more of the targets that are essential for yeast cell growth.

Amino Acid Sequence↗
PubMed2001

A point mutation in the juxtamembrane stalk of human angiotensin I-converting enzyme invokes the action of a distinct secretase.

Angiotensin I-converting enzyme (ACE) is one of a number of integral membrane proteins that is proteolytically shed from the cell surface by a zinc metallosecretase. Mutagenesis of Asn(631) to Gln in the juxtamembrane stalk region of ACE resulted in more efficient secretion of the mutant protein (ACE(NQ)) as determined by pulse-chase analysis. In contrast to the wild-type ACE, the cleavage of ACE(NQ) was not blocked by the metallosecretase inhibitor batimastat but by the serine protease inhibitor, 1,3-dichloroisocoumarin. Incubation of the cells at 15 degrees C revealed that ACE(NQ) was cleaved in the endoplasmic reticulum, and mass spectrometric analysis of the secreted form of the protein indicated that it had been cleaved at the Asn(635)-Ser(636) bond, three residues N-terminal to the normal secretase cleavage site at Arg(638)-Ser(639). These data clearly show that a point mutation in the juxtamembrane region of an integral membrane protein can invoke the action of a mechanistically and spatially distinct secretase. In light of this observation, previous data on the effect of mutations in the juxtamembrane stalk of shed proteins being accommodated by a single secretase having a relaxed specificity need to be re-evaluated.

Amino Acid Sequence↗
PubMed1999

Quantity of partial agonist activity for antiglucocorticoids complexed with mutant glucocorticoid receptors is constant in two different transactivation assays but not predictable from steroid structure.

An unsolved question in steroid hormone action is why the amount of agonist activity displayed by antisteroids is not constant but varies with the assay conditions. Receptor mutations have provided insight into hormone action, presumably due to changes in the tertiary structure of the receptor that alter its interaction surfaces with the transcriptional machinery or/and co-factors. We have now employed two mechanistically different induction assays to determine whether disparate transactivation processes are similarly altered by receptor mutations. The two activation assays studied were (i) the standard induction of GREtkLUC in transiently transfected CV-1 cells and (ii) a novel modulation of endogenous receptor activity by transiently transfected receptors in HeLa cells. Five different mutations in the ligand binding and DNA binding domains of the rat glucocorticoid receptor (CS1, CS1/CD, 451/9, C656G, and R732Q) and seven steroids of varied structures (five antagonists and two agonists) were selected for use. The results in both induction assays were the same. However, no generalizations regarding steroid structure and activity emerged. Neither of two potent glucocorticoids were active with GR-CS1, or GR-CS1/CD, while RU 486 was the only antisteroid with appreciable agonist activity. With the GR-451/9 mutant, three antagonists afforded partial agonist activity. We confirmed that the C656G mutant is both "super-sensitive" and "super-selective" for transactivation. In contrast, the R732Q mutation caused significant decreases in activity with both antagonists and subsaturating concentrations of agonists. This inability to generalize about the behavior of any class of steroids with mutant receptors may reflect an induced fit for each receptor steroid complex. Nevertheless, the activity of a given steroid appeared to be constant in two different transactivation assays for a given mutant receptor. Thus, disparate transactivation processes may utilize identical receptor surfaces, even in the expression of partial agonist activity for specific antiglucocorticoids.

Amino Acid Substitution↗
PubMed2005

A key serine for the GTPase-activating protein function of regulator of G protein signaling proteins is not a general target for 14-3-3 interactions.

Mammalian regulator of G protein signaling (RGS) proteins are highly conserved within the RGS domain. Of amino acids that are universal, a serine residue at the C terminus of this domain has been described as the binding site in RGS7 for 14-3-3 proteins. However, studies with the related RGS3 indicate that the site of interaction is not within the RGS domain. We confirm that the interaction of RGS3 with 14-3-3tau and 14-3-3zeta requires Ser264 and not the RGS domain and show both that mutation of the conserved RGS domain serine, Ser496 in RGS3, to either alanine or aspartate does not prevent binding of 14-3-3 proteins and that 14-3-3 proteins do not inhibit GTPase-activating protein (GAP) activity against receptor-activated Galpha(o1). However, mutation of Ser496 does directly impair the action of RGS3 as a GAP against receptor-activated Galpha(o1). We mutated the equivalent serine residue in the family B/R4 RGS proteins RGS1 and RGS16. Using two distinct assay formats, conversion to aspartate virtually abolished GAP activity, whereas conversion to alanine decreased potency 20-fold. Neither alteration modulated interactions with 14-3-3tau or 14-3-3zeta, but the 14-3-3 proteins did not modulate the GAP activity of the wild-type or mutant RGS proteins. Although interactions between 14-3-3 proteins and many RGS proteins can be observed, this does not involve this conserved serine and does not inherently modify GAP function.

14-3-3 Proteins↗
PubMed2006

Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene.

AIMS/HYPOTHESIS: Recently we reported the coexistence of postprandial hypoglycaemia and moderate insulin resistance in heterozygous carriers of the Arg1174Gln mutation in the insulin receptor gene (INSR). Controlled studies of in vivo insulin signalling in humans with mutant INSR are unavailable, and therefore the cellular mechanisms underlying insulin resistance in Arg1174Gln carriers remain to be clarified. SUBJECTS, MATERIALS AND METHODS: We studied glucose metabolism and insulin signalling in skeletal muscle from six Arg1174Gln carriers and matched control subjects during a euglycaemic-hyperinsulinaemic clamp. RESULTS: Impaired clearance of exogenous insulin caused four-fold higher clamp insulin levels in Arg1174Gln carriers compared with control subjects (p<0.05). In Arg1174Gln carriers insulin increased glucose disposal and non-oxidative glucose metabolism (p<0.05), but to a lower extent than in controls (p<0.05). Insulin increased Akt phosphorylation at Ser473 and Thr308, inhibited glycogen synthase kinase-3alpha activity, reduced phosphorylation of glycogen synthase at sites 3a+3b, and increased glycogen synthase activity in Arg1174Gln carriers (all p<0.05). In the insulin-stimulated state, Akt phosphorylation at Thr308 and glycogen synthase activity were reduced in Arg1174Gln carriers compared with controls (p<0.05), whereas glycogen synthase kinase-3alpha activity and phosphorylation of glycogen synthase at sites 3a+3b were similar in the two groups. CONCLUSIONS/INTERPRETATION: In vivo insulin signalling in skeletal muscle of patients harbouring the Arg1174Gln mutation is surprisingly intact, with modest impairments in insulin-stimulated activity of Akt and glycogen synthase explaining the moderate degree of insulin resistance. Our data suggest that impaired insulin clearance in part rescues in vivo insulin signalling in muscle in these carriers of a mutant INSR, probably by increasing insulin action on the non-mutated insulin receptors.

Adult↗
PubMed2003

Action potential changes associated with a slowed inactivation of cardiac voltage-gated sodium channels by KB130015.

1. We have studied the acute cardiac electrophysiological effects of KB130015 (KB), a drug structurally related to amiodarone. Membrane currents and action potentials were measured at room temperature or at 37 degrees C during whole-cell patch-clamp recording in ventricular myocytes. Action potentials were also measured at 37 degrees C in multicellular ventricular preparations. 2. The effects of KB were compared with those of anemone toxin II (ATX-II). Both KB and ATX-II slowed the inactivation of the voltage-gated Na(+) current (I(Na)). While KB shifted the steady-state voltage-dependent inactivation to more negative potentials, ATX-II shifted it to more positive potentials. In addition, while inactivation proceeded to completion with KB, a noninactivating current was induced by ATX-II. 3. KB had no effect on I(K1) but decreased I(Ca-L) The drug also did not change I(to) in mouse myocytes. 4. The action potential duration (APD) in pig myocytes or multicellular preparations was not prolonged but often shortened by KB, while marked APD prolongation was obtained with ATX-II. Short APDs in mouse were markedly prolonged by KB, which frequently induced early afterdepolarizations. 5. A computer simulation confirmed that long action potentials with high plateau are relatively less sensitive to a mere slowing of I(Na) inactivation, not associated with a persisting, noninactivating current. In contrast, simulated short action potentials with marked phase-1 repolarization were markedly modified by slowing I(Na) inactivation. 6 It is suggested that a prolongation of short action potentials by drugs or mutations that only slow I(Na) inactivation does not necessarily imply identical changes in other species or in different myocardial regions.

Action Potentials↗
PubMedDate not supplied

[Some properties of a mutant of Streptomyces globisporus 1912 supersensitive to ultraviolet radiation].

A well-sporulating mutant Spo 1 has been isolated after the action of defective phage from the zone of total lysis of Streptomyces globisporus 1912. It has been shown, that mutant Spo 1 is supersensitive to the action of ultraviolet radiation and has the increased sensitivity to the action of methyl-methane-sulfonate, has mutation in the cluster of genes of synthesis of landomycin E and is not sensitive to the action of nitrous acid and hydrogen peroxide. Spo 1 also has a high level of UV-mutability. After the action of UV on spores 4620 colonies were analysed and 17 auxotrophic mutants (0.36%) were selected. Four auxotrophs restored their ability to produce landomycin E and a partial block of synthesis of the antibiotic was observed in six auxotrophs. Seven of white (lnd E) auxotrophs were analysed with the help of a system "secretor-conventer" and it has been shown that two mutants do not synthesize daidzeine flavonoide and have genotype lnd E dai aux uvs, five of them were capable to synthesize this flavonoide and have genotype lnd dai(+) aux uvs. Initial species of S. globisporus 1912 has increased sensitivity to lethal action of UV. It is supposed that mutant Spo 1 bears two uvs-mutations.

Aminoglycosides↗
PubMed2026

Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC): An Aggressive Disease Course and Limitations for Personalized Oncology.

Neuroendocrine carcinoma (NEC) is a rare, aggressive malignancy with limited treatment options and poor prognosis. We report a male patient diagnosed with a gastroenteropancreatic (GEP)-NEC with synchronous liver metastasis at the time of surgery who underwent a radical resection attempt. Despite radical-intent surgery followed by adjuvant carboplatin/etoposide, early recurrence developed with progression through multiple subsequent chemotherapy lines. During the treatment process, genetic profiling was&#xa0;performed twice to identify actionable genomic targets, with inclusion in the national IMPRESS study as a last resort. Comprehensive genomic profiling revealed TP53 mutation and RB1 loss but no actionable alterations. A patient-derived organoid (PDO) was successfully established from resected tumor tissue and retained key neuroendocrine and proliferative features, with partial genomic concordance to the primary tumor. Differences between the primary and subsequent PDO in variant allele frequencies suggest clonal selection during culture. Exploratory metabolomic profiling of tryptophan pathway metabolites in patient serum and PDO-culture media indicated tumor-associated metabolic alterations. We present clinical and translational efforts in difficult-to-treat NEC, illustrating both the translational challenges and the potential role of PDOs in advancing personalized treatment strategies for a cancer with very limited treatment options.

Gastroenteropancreatic neuroendocrine carcinoma↗
PubMed2004

Aryl hydrocarbon receptors in urogenital sinus mesenchyme mediate the inhibition of prostatic epithelial bud formation by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

In utero exposure of male C57BL/6 mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prevents prostatic epithelial buds from forming in the ventral region of the urogenital sinus (UGS) and reduces the number of buds that form in the dorsolateral region. This inhibition of budding is aryl hydrocarbon receptor (AHR) dependent and appears to be the primary cause of lobe-specific prostate abnormalities in TCDD-exposed mice. TCDD can inhibit prostatic epithelial bud formation by acting directly on the UGS in vitro, but whether it does so via AHR in UGS mesenchyme, epithelium, or both was unknown. To address this issue, UGS mesenchyme and epithelium from gestation day (GD) 15 wild-type C57BL/6J male mice were isolated, recombined, and cultured in vitro for 5 days with 10(-8) M 5alpha-dihydrotestosterone (DHT) and either 10(-9) M TCDD or vehicle. Prostatic epithelial buds were viewed by light microscopy after removal of mesenchyme. Effects depended greatly on which portions of the mesenchyme were used: TCDD had little if any effect when whole UGS epithelium (UGE) was recombined with ventral plus dorsolateral mesenchyme, tended to reduce bud numbers in recombinants made with UGE and dorsolateral mesenchyme, and severely reduced bud numbers in recombinants made with UGE and ventral mesenchyme (VM). [VM + UGE] recombinants prepared from wild-type and AHR knockout (Ahr(-/-)) mice were then cultured with DHT to determine the site of action of TCDD. AHR null mutation alone had no effect on budding. TCDD severely inhibited prostatic epithelial bud formation in recombinants that contained mesenchymal AHR, whereas bud formation was not inhibited by TCDD in recombinants lacking mesenchymal AHR, regardless of epithelial AHR status. These results demonstrate that UGS mesenchyme and not UGS epithelium is the site of action of TCDD. Therefore, the initial events responsible for abnormal UGS (and ultimately prostate) development occur within the UGS mesenchyme, and changes in gene expression in the UGS epithelium responsible for inhibited prostatic budding are secondary to the direct effects of TCDD on UGS mesenchyme.

Animals↗
PubMed1980

Genetics of penicillin titre in lines of Aspergillus nidulans selected through recurrent mutagenesis.

Genetic analyses of mutations for increased penicillin titre were carried out on two strains of Aspergillus nidulans isolated after independent programmes of recurrent mutation and selection, similar to those used industrially for strain improvement. Both selected strains were stable in terms of colony morphology and penicillins titre. Backcrosses to the unselected ancestor indicated that the increased yield of each strain was due to an induced polygenic system with both additive and non-additive gene action. The titre-increasing mutations in one strain (A6-9) were recessive to their wild-type alleles, while those in the other (B6-27) were either semi-dominant or showed ambidirectional dominance. The diploid between A6-9 and B6-27 had a titre less than either component haploid, suggesting that the mutations in the two strains involved different genes. Strain B6-27 carried a translocation between chromosomes III and VII which had been induced during the selection programme. This investigation complements previous work on the genetics of penicillin production in A. nidulans and Penicillium chrysogenum and the results are directly relevant to industrial strain improvement by hybridization of divergent strains.

Alleles↗
PubMed1981

Speed-accuracy relationships during in vitro and in vivo protein biosynthesis.

Poly U-directed incorporation of phenylalanine and leucine into polypeptide has been described in at least 50 papers since 1961. In general, high translation activities are associated with high accuracies, and vice-versa. Moreover, a vast body of independent experimental data (effect of ethanol, temperature, urea, aminoglycosides, etc... on protein synthesis) put together here suggests that, in many circumstances, speed and accuracy of elongation are correlated. This result is to be contrasted with the view that the speed and the fidelity of protein synthesis are two opposing parameters. In this report, recent experimental data on the nature and effect of ribosomal ambiguity (ram) and streptomycin resistance (Strr) mutations are reexamined. Models on the action of streptomycin and other misreading-inducing antibiotics, as well as long-standing ideas on the control of misreading in mammalian systems are critically evaluated. An explanation is provided for the long-befuddling data on the action of gentamicin.

Animals↗
PubMed2004

Identification of negative residues in the P2X3 ATP receptor ectodomain as structural determinants for desensitization and the Ca2+-sensing modulatory sites.

On nociceptive neurons, one important mechanism to generate pain signals is the activation of P2X(3) receptors, which are membrane proteins gated by extracellular ATP. In the presence of the agonist, P2X(3) receptors rapidly desensitize and then recover slowly. One unique property of P2X(3) receptors is the recovery acceleration by extracellular Ca(2+) that can play the role of the gain-setter of receptor function only when P2X(3) receptors are desensitized. To study negatively charged sites potentially responsible for this action of Ca(2+), we mutated 15 non-conserved aspartate or glutamate residues in the P2X(3) receptor ectodomain with alanine and expressed such mutated receptors in human embryonic kidney cells studied with patch clamping. Unlike most mutants, D266A (P2X(3) receptor numbering) desensitized very slowly, indicating that this residue is important for generating desensitization. Recovery appeared structurally distinct from desensitization because E111A and D266A had a much faster recovery and D220A and D289A had a much slower one despite their standard desensitization. Furthermore, E161A, E187A, or E270A mutants showed lessened sensitivity to the action of extracellular Ca(2+), suggesting that these determinants were important for the effect of this cation on desensitization recovery. This study is the first report identifying several negative residues in the P2X(3) receptor ectodomain differentially contributing to the general process of receptor desensitization. At least one residue was important to enable the development of rapid desensitization, whereas others controlled recovery from it or the facilitating action of Ca(2+). Thus, these findings outline diverse potential molecular targets to modulate P2X(3) receptor function in relation to its functional state.

Adenosine Triphosphate↗
PubMed2005

Molecular pathology of the androgen receptor in male (in)fertility.

Idiopathic male infertility, accounting for 40% of all male infertility cases, is postulated to have a genetic basis. The androgen receptor (AR) plays a crucial post-meiotic role during male germ cell differentiation, which includes terminal differentiation of spermatids and their release from the seminiferous epithelium. Mutations in the AR gene result in a condition known as androgen insensitivity syndrome (AIS) affecting normal male morphogenesis. Depending on the severity of the syndrome, the external phenotype can range from normal female to normal male. In almost all cases affected individuals are infertile. In seven reported cases individuals appeared to suffer primarily or solely from male infertility, suggesting these AR mutations specifically cause male infertility. Three of these mutations are possibly population specific. Longer CAG repeats present in exon 1 of the AR have been studied as a possible risk factor for male infertility. Results are contradictory, with a trend to significance (Asian populations) and non-significance (European populations). Recent advances in protein modelling techniques may result in a much better understanding of the mechanism of action of the known infertility mutations. The determination of the significance of longer CAG repeats is likely to require studies that examine CAG repeat lengths in spermatozoa as well as patients' blood.

Androgen-Insensitivity Syndrome↗