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PubMed1998

Changes in auxin response from mutations in an AUX/IAA gene.

Transcription of the AUX/IAA family of genes is rapidly induced by the plant hormone auxin, but evidence that AUX/IAA genes mediate further responses to auxin has been elusive. Changes in diverse auxin responses result from mutations in the Arabidopsis AXR3 gene. AXR3 was shown to be a member of the AUX/IAA family, providing direct evidence that AUX/IAA genes are central in auxin signaling. Molecular characterization of axr3 gain-of-function and loss-of-function mutations established the functional importance of domains conserved among AUX/IAA proteins.

Amino Acid Sequence↗
PubMed2000

Molecular analysis of LHX3 and PROP-1 in pituitary hormone deficiency patients with posterior pituitary ectopia.

The cause of posterior pituitary ectopia associated with anterior pituitary hormone deficiencies is unknown. We describe children with combined pituitary hormone deficiency (CPHD) or isolated GH deficiency. In all cases, magnetic resonance imaging examination revealed abnormal pituitary gland development featuring ectopic posterior lobe location and frequently hypoplastic anterior lobes. Embryonic development of the pituitary requires the coordinated expression of specific transcription factors. Mutations of the PIT-1 and PROP-1 transcription factors are responsible for CPHD in some patients with normally positioned posterior pituitaries. In mice, the Lhx3 LIM homeodomain transcription factor is required for both structural development and cellular differentiation of the pituitary gland. Thus, we hypothesized that mutations in one or both of the two human LHX3 isoforms are responsible for posterior pituitary ectopia associated with anterior pituitary hypopituitarism. Comprehensive molecular analysis of the LHX3 isoforms was performed to test this hypothesis. No loss of function mutations in the LHX3 gene were detected. In addition, analysis of PROP-1 did not reveal mutations that might cause this phenotype. These studies suggest that the abnormal processes leading to the development of CPHD or GH deficiency associated with posterior pituitary ectopia are not a result of aberrant LHX3 or PROP- 1 function, but may be caused by defects at other gene loci.

Animals↗
PubMed2004

Oncogenic K-ras in mouse models of myeloproliferative disease and acute myeloid leukemia.

Oncogenic N-RAS and K-RAS mutations are among the most frequently detected genetic alterations in patients with acute myeloid leukemia (AML). Recently, the role of oncogenic K-ras in leukemogenesis was investigated in a novel mouse model utilizing interferon (IFN)-inducible, Cre-mediated expression of oncogenic K-ras from its endogenous promoter. Conditional expression of oncogenic K-ras from its endogenous promoter in the hematopoietic system induces a lethal myeloproliferative disease in mice, but not AML, indicating that additional mutations are required for AML development. These results are consistent with a model in which the AML phenotype requires at least two cooperating mutations in the hematopoietic progenitor cells: one promoting proliferation and enhanced cell survival (such as oncogenic ras or a constitutively activated receptor tyrosine kinase) and one associated with impaired differentiation and enhanced immortalization (such as loss-of-function mutations in hematopoietic transcription factors). The model system with oncogenic K-ras provides a versatile platform to test the contribution of cooperating mutations in AML, and the efficacy of Ras pathway inhibitors in vivo.

Animals↗
PubMed2005

A novel splice-site mutation in ECM-1 gene in a consanguineous family with lipoid proteinosis.

Lipoid proteinosis (LP) (OMIM 247100) is a rare, autosomal recessive disorder. Recent studies have shown that LP is the result of reduced expression of the extracellular matrix protein gene (ECM-1), in which loss-of-function mutations have been described. In the present report, we describe a large consanguineous family with LP. We identified a homozygous splice-site mutation in intron 1 (IVS1 + 1G-->C) in three clinically affected patients. This is the first splice-site mutation reported in LP and is the most 5' of all ECM-1 mutations described thus far. It is predicted to result in the removal of the translation initiation site, thus ablating all three known ECM-1 isoforms (ECM-1a, ECM-1b, and ECM-1c). In addition, we found a novel splicing variant that is not associated with the disease (DQ010946) and results in the generation of a short, prematurely terminating transcript. This case further emphasizes the role of ECM-1 in LP and highlights the unresolved genotype-phenotype correlation in this disease.

Adolescent↗
PubMed2005

Belle is a Drosophila DEAD-box protein required for viability and in the germ line.

DEAD-box proteins are ATP-dependent RNA helicases that function in various stages of RNA processing and in RNP remodeling. Here, we report identification and characterization of the Drosophila protein Belle (Bel), which belongs to a highly conserved subfamily of DEAD-box proteins including yeast Ded1p, Xenopus An3, mouse PL10, human DDX3/DBX, and human DBY. Mutations in DBY are a frequent cause of male infertility in humans. Bel can substitute in vivo for Ded1p, an essential yeast translation factor, suggesting a requirement for Bel in translation initiation. Consistent with an essential cellular function, strong loss of function mutations in bel are recessive lethal with a larval growth defect phenotype. Hypomorphic bel mutants are male-sterile. Bel is also closely related to the Drosophila DEAD-box protein Vasa (Vas), a germ line-specific translational regulator. We find that Bel and Vas colocalize in nuage and at the oocyte posterior during oogenesis, and that bel function is required for female fertility. However, unlike Vas, Bel is not specifically enriched in embryonic pole cells. We conclude that the DEAD-box protein Bel has evolutionarily conserved roles in fertility and development.

Amino Acid Sequence↗
PubMed2006

Filaggrin mutations p.R501X and c.2282del4 in ichthyosis vulgaris.

Ichthyosis vulgaris (IV) is the most common hereditary disorder of cornification in humans, characterized by generalized fine scaling of the skin, palmar hyperlinearity with or without keratosis pilaris and atopy. Recently, the molecular basis of IV was ascribed to loss-of-function mutations in the gene encoding filaggrin (FLG), namely p.R501X and c.2282del4. Homozygotes and compound heterozygotes were severely affected whereas heterozygotes showed mild disease or were asymptomatic, suggesting semidominant inheritance with incomplete penetrance in heterozygotes. We report the presence of FLG mutations in 15 out of 21 IV patients with a marked generalized scaling phenotype, including eight affected members of a four-generation family. In this group of patients not only homozygous and compound heterozygous, but also heterozygous patients for p.R501X and c.2282del4 display a pronounced phenotype, whereas in none of six individuals these two mutations were detectable despite decreased filaggrin expression on immunohistochemistry in two patients, indicating that other mutations in FLG and/or in other genes remain to be identified. In contrast, two additional p.R501X heterozygotes from the extended family are asymptomatic. In a control population from west-Austria a combined p.R501X and c.2282del4 carrier frequency of 6/110 (5.45%) was observed. We confirm that these FLG variants are common, but our results point to the existence of additional modifiers.

Austria↗
PubMed1997

Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia.

Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability. By analysing tumour DNA from patients with sporadic T-cell prolymphocytic leukaemia (T-PLL), a rare clonal malignancy with similarities to a mature T-cell leukaemia seen in A-T, we demonstrate a high frequency of ATM mutations in T-PLL. In marked contrast to the ATM mutation pattern in A-T, the most frequent nucleotide changes in this leukaemia were missense mutations. These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast and Drosophila. The resulting amino-acid substitutions are predicted to interfere with ATP binding or substrate recognition. Two of seventeen mutated T-PLL samples had a previously reported A-T allele. In contrast, no mutations were detected in the p53 gene, suggesting that this tumour suppressor is not frequently altered in this leukaemia. Occasional missense mutations in ATM were also found in tumour DNA from patients with B-cell non-Hodgkin's lymphomas (B-NHL) and a B-NHL cell line. The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor. As constitutional DNA was not available, a putative hereditary predisposition to T-PLL will require further investigation.

Amino Acid Sequence↗
PubMed1995

Requirements for strand- and site-specific cleavage within the oriT region of Tn4399, a mobilizing transposon from Bacteroides fragilis.

Replicons that contain Tn4399, a conjugal mobilizing transposon isolated from Bacteroides fragilis, can be mobilized in the presence of broad-host-range IncP plasmids RP4 and R751 in Escherichia coli to B. fragilis or E. coli recipients (C. G. Murphy and M. H. Malamy, J. Bacteriol. 175:5814-5823, 1993). To identify the initial DNA processing events involved in Tn4399-mediated mobilization in E. coli, plasmid DNA from pCGM328 (a pUC7 vector that contains the mobilization region of Tn4399) was isolated from donor cells following the release of plasmid DNA from the relaxation complex. Site- and strand-specific cleavage within the oriT region of Tn4399 was detected by denaturing gel electrophoresis and Southern hybridization analysis of this DNA in the presence or absence of IncP plasmids. Mutations in either mocA or mocB, two genes which are encoded by Tn4399 and are required for mobilization, significantly decrease the amount of specifically nicked DNA detected. These results suggest roles for the MocA and MocB gene products in specific processing of Tn4399-containing plasmid DNA prior to mobilization. By isolation of the nicked strand and primer extension of this template, we mapped the precise 5' end of the single-stranded cleavage reaction. The nucleotide position of nicTn4399 is adjacent to two sets of inverted repeats, a genetic arrangement similar to those of previously characterized oriT regions. Two site-directed mutations which remove nicTn4399 (oriT delta 1 and oriT delta 2) cannot be mobilized to recipients when they are present in trans along with functional MocA and MocB proteins and an IncP mobilizing plasmid; they are cis-dominant loss-of-function mutations.

Bacterial Proteins↗
PubMed2006

The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1).

Mutations in VMD2, encoding bestrophin (best-1), cause Best vitelliform macular dystrophy (BMD), adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC). BMD is distinguished from AVMD by a diminished electrooculogram light peak (LP) in the absence of changes in the flash electroretinogram. Although the LP is thought to be generated by best-1, we find enhanced LP luminance responsiveness with normal amplitude in Vmd2-/- mice and no differences in cellular Cl- currents in comparison to Vmd2+/+ littermates. The putative Ca2+ sensitivity of best-1, and our recent observation that best-1 alters the kinetics of voltage-dependent Ca2+ channels (VDCC), led us to examine the role of VDCCs in the LP. Nimodipine diminished the LP, leading us to survey VDCC beta-subunit mutant mice. Lethargic mice, which harbor a loss of function mutation in the beta4 subunit of VDCCs, exhibited a significant shift in LP luminance response, establishing a role for Ca2+ in LP generation. When stimulated with ATP, which increases [Ca++]I, retinal pigment epithelial cells derived from Vmd2-/- mice exhibited a fivefold greater response than Vmd2+/+ littermates, indicating that best-1 can suppress the rise in [Ca2+]I associated with the LP. We conclude that VDCCs regulated by a beta4 subunit are required to generate the LP and that best-1 antagonizes the LP luminance response potentially via its ability to modulate VDCC function. Furthermore, we suggest that the loss of vision associated with BMD is not caused by the same pathologic process as the diminished LP, but rather is caused by as yet unidentified effects of best-1 on other cellular processes.

Adenosine Triphosphate↗
PubMedDate not supplied

Misrouted cell surface GnRH receptors as a disease aetiology for congenital isolated hypogonadotrophic hypogonadism.

GnRH plays an essential and central role in neuroendocrine control of reproductive function. The GnRH receptor is located on the plasma membrane of gonadotrophs, pituitary cells that synthesize the gonadotrophins LH and FSH. This receptor belongs to the superfamily of G protein-coupled receptors, and is preferentially coupled to the G(q/11) protein; its activation by GnRH analogues stimulates the synthesis and release of LH and FSH. Resistance to GnRH by inactivating (loss-of-function) mutations of the human GnRH receptor leads to distinct forms of sporadic or inherited hypogonadotrophic hypogonadism. Although in vitro expression of a number of these mutated GnRH receptors in heterologous systems has shown that these mutations appear to alter several functions of the molecule, including ligand binding, receptor activation or interaction with coupled effectors, recent observations from our laboratory have challenged this view and indicated that protein misfolding and resultant misrouting is a mechanism that, by itself, may lead to loss of function of the human GnRH receptor. In this review we describe the experimental data that led us to this conclusion and how these studies revealed previously unsuspected features of the mutant human GnRH receptor.

Amino Acid Sequence↗
PubMed2000

Arteriovenous malformations in mice lacking activin receptor-like kinase-1.

The mature circulatory system is comprised of two parallel, yet distinct, vascular networks that carry blood to and from the heart. Studies have suggested that endothelial tubes are specified as arteries and veins at the earliest stages of angiogenesis, before the onset of circulation. To understand the molecular basis for arterial-venous identity, we have focused our studies on a human vascular dysplasia, hereditary haemorrhagic telangiectasia (HHT), wherein arterial and venous beds fail to remain distinct. Genetic studies have demonstrated that HHT can be caused by loss-of-function mutations in the gene encoding activin receptor-like kinase-1 (ACVRL1; ref. 5). ACVRL1 encodes a type I receptor for the TGF-beta superfamily of growth factors. At the earliest stage of vascular development, mice lacking Acvrl1 develop large shunts between arteries and veins, downregulate arterial Efnb2 and fail to confine intravascular haematopoiesis to arteries. These mice die by mid-gestation with severe arteriovenous malformations resulting from fusion of major arteries and veins. The early loss of anatomical, molecular and functional distinctions between arteries and veins indicates that Acvrl1 is required for developing distinct arterial and venous vascular beds.

Activin Receptors↗
PubMed2000

Functional analysis of Cdc42 in actin filament assembly, epithelial morphogenesis, and cell signaling during Drosophila development.

Cdc42, a member of the Rho family of GTP binding proteins, functions in the formation of polarized actin structures, in elongation of cell shape, and in cell signaling. Although genetic mutations previously have not been available in multicellular organisms, studies have attempted to discern Cdc42 functions in organisms, including Drosophila, using dominant active or interfering alleles. Here, for the first time, we examine the functions of Cdc42 in developing tissues using loss-of-function mutations in the Drosophila Cdc42 gene. We find that Cdc42(-) epithelial cells fail to elongate into a columnar cell shape and cannot maintain a monolayered epithelial structure. In contrast to previous studies, we find no requirement for Cdc42 in cell division or in activation of the Jun N-terminal kinase pathway. In addition, Cdc42 function is not required for cytoplasmic actin filament assembly in the nurse cells during oogenesis, although it may facilitate this process. Furthermore, our results indicate that Cdc42 plays a role in intercellular interactions between the germ line and the somatic follicle cells. These results confirm the role of Cdc42 in actin filament assembly and provide new insights into its functions in epithelial morphogenesis and regulating intercellular signaling events.

Actins↗
PubMed2006

Microcephaly and simplified gyral pattern of the brain associated with early onset insulin-dependent diabetes mellitus.

Two families are presented with a child suffering from microcephaly with a simplified gyral pattern of the brain (SGP) and early onset insulin dependent diabetes mellitus (IDDM). The first patient was diagnosed postmortally with Wolcott-Rallison syndrome, after her younger brother developed IDDM, and a homozygous mutation in the eukaryotic translation initiation factor 2-alpha kinase 3 was found. The younger brother did not undergo magnetic resonance imaging (MRI). The patient from the second family has no EIF2AK3 mutation. SGP is considered to arise from decreased neuronal proliferation or increased apoptosis at an early stage of embryonal development, but insight into the pathways involved is minimal. EIF2AK3 is involved in translation initiation. It has been proposed that loss of function mutations reduce the ability of the cell to respond to endoplasmic reticulum stress, resulting in apoptosis of pancreatic Langerhans cells. Our findings suggest that in some cases, early onset IDDM and SGP can arise from common mechanisms leading to increased apoptosis.

Age of Onset↗
PubMed2001

Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production.

Single-gene mutations that extend lifespan provide valuable tools for the exploration of the molecular basis for age-related changes in cell and tissue function and for the pathophysiology of age-dependent diseases. We show here that mice homozygous for loss-of-function mutations at the Pit1 (Snell dwarf) locus show a >40% increase in mean and maximal longevity on the relatively long-lived (C3H/HeJ x DW/J)F(1) background. Mutant dw(J)/dw animals show delays in age-dependent collagen cross-linking and in six age-sensitive indices of immune system status. These findings thus demonstrate that a single gene can control maximum lifespan and the timing of both cellular and extracellular senescence in a mammal. Pituitary transplantation into dwarf mice does not reverse the lifespan effect, suggesting that the effect is not due to lowered prolactin levels. In contrast, homozygosity for the Ghrhr(lit) mutation, which like the Pit1(dw) mutation lowers plasma growth hormone levels, does lead to a significant increase in longevity. Male Snell dwarf mice, unlike calorically restricted mice, become obese and exhibit proportionately high leptin levels in old age, showing that their exceptional longevity is not simply due to alterations in adiposity per se. Further studies of the Pit1(dw) mutant, and the closely related, long-lived Prop-1(df) (Ames dwarf) mutant, should provide new insights into the hormonal regulation of senescence, longevity, and late life disease.

Aging↗
PubMed2003

Familial Parkinson's disease-associated L166P mutation disrupts DJ-1 protein folding and function.

Mutations in DJ-1, a protein of unknown function, were recently identified as the cause for an autosomal recessive, early onset form of familial Parkinson's disease. Here we report that DJ-1 is a dimeric protein that exhibits protease activity but no chaperone activity. The protease activity was abolished by mutation of Cys-106 to Ala, suggesting that DJ-1 functions as a cysteine protease. Our studies revealed that the Parkinson's disease-linked L166P mutation impaired the intrinsic folding propensity of DJ-1 protein, resulting in a spontaneously unfolded structure that was incapable of forming a homodimer with itself or a heterodimer with wild-type DJ-1. Correlating with the disruption of DJ-1 structure, the L166P mutation abolished the catalytic function of DJ-1. Furthermore, as a result of protein misfolding, the L166P mutant DJ-1 was selectively polyubiquitinated and rapidly degraded by the proteasome. Together these findings provide insights into the molecular mechanism by which loss-of-function mutations in DJ-1 lead to Parkinson's disease.

Amino Acid Sequence↗
PubMed1997

Hirschsprung's disease: genetic mutations in mice and men.

Hirschsprung's disease is a neuronal dysplasia of the hindgut, characterised by a loss of neurones, which affects about 1 in 5000 live births. Genetic factors have been implicated in the aetiology of this disease in about 20% of cases and a dominant pattern of inheritance has been revealed in several families. The pathogenesis of the aganglionosis is often attributed to a failure of migration of neural crest cells, although this has not been proven. Recently, mutations in a developmentally regulated receptor tyrosine kinase gene, ret, and mutations in the endothelin receptor-B gene (ENDR-B) have both been linked to familial Hirschsprung's disease in humans. Moreover, certain mutant mouse strains--namely piebald lethal and lethal spotted--exhibit striking similarities to the human condition. The mutation which gives rise to piebald lethal has now been found to be in the ENDR-B gene, and the mutation associated with lethal spotted occurs in the gene for endothelin-3 (ET-3), a ligand for ENDR-B. Two transgenic mouse lines have been developed which also reflect the human disease: ret-k-, which has a loss of function mutation of the ret gene, and ENDR-B null. In addition, the introduction of a Lac-Z reporter gene into neural crest cells of aganglionic mice has made it possible to study directly the fate of enteric neuroblasts which are affected by "Hirschsprung's-like" mutations. Here, we review the possible roles of RET and endothelin in the normal development of the enteric nervous system, and the significance of their mutated forms in the pathogenesis of familial aganglionosis. This review focuses on recent advances in our understanding of the genetic basis of the lesions which have been implicated in congenital forms of Hirschsprung's disease. Disruption of these genes in the mouse, either by transgenic "knockout" approaches or in mutant mouse lines, offers the prospect of greater understanding of both the cellular and developmental bases of the human disease.

Animals↗
PubMed1998

Reduced expression of pax-3 is associated with overexpression of cdc46 in the mouse embryo.

CDC46/MCM5 encodes a protein that is highly conserved among yeast, plants, and animals. It is found in a complex which exhibits DNA replication licensing activity, which is proposed to regulate the synthesis of DNA once and only once per cell cycle. In yeast, loss of function mutations of CDC46/MCM5 decrease DNA synthesis. Very little is known about the regulation of CDC46/MCM5 in any species. We report here that, in the mouse embryo, expression of cdc46 is increased in unfused portions of the neural tube when the gene encoding the transcription factor, Pax-3, is either nonfunctional or underexpressed. These results were observed both in embryos of diabetic mice, which we have previously shown express significantly reduced levels of Pax-3 mRNA, and in Splotch embryos, which carry loss of function Pax-3 alleles. This indicates that expression of cdc46 is negatively regulated as part of a Pax-3-dependent pathway. Since cdc46 appears to regulate DNA synthesis and cell cycle progression, it is possible that its overexpression is involved in defective embryonic development that is associated with loss of Pax-3 function.

Alleles↗
PubMed2004

Congenital primary hypothyroidism in a turkish family caused by a homozygous nonsense mutation (R609X) in the thyrotropin receptor gene.

Congenital primary hypothyroidism can be caused by reduced or absent responsiveness of the thyroid gland to thyrotropin (TSH), which normally binds to the thyrotropin receptor (TSHR) and exerts its effects mainly by stimulating intracellular cyclic adenosine monophosphate (cAMP). So far 22 causative loss-of-function mutations in the TSHR gene have been reported as occurring in families from different ethnic and geographical origins. We here report a family of Turkish origin in which all four children were diagnosed as having congenital primary hypothyroidism. A homozygous nonsense mutation in codon 609 (R609X) of the TSHR gene was identified in all affected individuals as the underlying molecular defect. The mutation leads to a truncated TSHR, which is likely to be biologically inactive. This mutation has been identified before to cause resistance to TSH in a large Bedouin kindred where two affected hypothyroid individuals were also resistant to adrenocorticotrophic hormone (ATCH). Interestingly none of the affected individuals in our family had symptoms consistent with hypocortisolism, which excludes a direct impact of this TSHR mutation on the hypothalamicpituitary-adrenal axis.

Amino Acid Sequence↗