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PubMed2002

Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm.

A loss-of-function mutation in the mouse delta-like3 (Dll3) gene has been generated following gene targeting, and results in severe axial skeletal defects. These defects, which consist of highly disorganised vertebrae and costal defects, are similar to those associated with the Dll3-dependent pudgy mutant in mouse and with spondylocostal dysplasia (MIM 277300) in humans. This study demonstrates that Dll3(neo) and Dll3(pu) are functionally equivalent alleles with respect to the skeletal dysplasia, and we suggest that the three human DLL3 mutations associated with spondylocostal dysplasia are also functionally equivalent to the Dll3(neo) null allele. Our phenotypic analysis of Dll3(neo)/Dll3(neo) mutants shows that the developmental origins of the skeletal defects lie in delayed and irregular somite formation, which results in the perturbation of anteroposterior somite polarity. As the expression of Lfng, Hes1, Hes5 and Hey1 is disrupted in the presomitic mesoderm, we suggest that the somitic aberrations are founded in the disruption of the segmentation clock that intrinsically oscillates within presomitic mesoderm.

Alleles↗
PubMed2005

Disorders of sexual development caused by luteinizing hormone receptor mutations.

The Luteinizing hormone/chorionic gonadotropin receptor (LHR) plays a critical role in human male sexual development. Both gain-of-function and loss-of-function mutations of the LHR have been described. Gain-of-function mutations are dominant and cause constitutive activation of the receptor resulting in familial male-limited precocious puberty (FMPP). All activating mutations are single point mutations and are located in the transmembrane domain (TM). TM helix VI harbors the largest number of activating mutations with the codon of Asp-578 being the hot-spot of mutation. Besides causing abnormal sexual development, constitutively activated LHR may predispose an individual to the development of testicular neoplasia. The anti-thesis of FMPP is Leydig cell hypoplasia (LCH). This is caused by mutations that inactivate the LHR resulting in subnormal male sexual development or male pseudohermaphroditism. Inactivating mutations are recessive. The genetic cause of LCH is variable and there is no mutation hot-spot. Genotype-phenotype correlation can be identified in LCH with the milder form caused by mutated LHR with residual activity and the severe form caused by absence of signal transduction activity of the mutated receptor. Molecular diagnosis of the disorders caused by mutation of the LHR can be achieved by direct sequencing of the LHR gene.

Child↗
PubMed2004

Drosophila spastin regulates synaptic microtubule networks and is required for normal motor function.

The most common form of human autosomal dominant hereditary spastic paraplegia (AD-HSP) is caused by mutations in the SPG4 (spastin) gene, which encodes an AAA ATPase closely related in sequence to the microtubule-severing protein Katanin. Patients with AD-HSP exhibit degeneration of the distal regions of the longest axons in the spinal cord. Loss-of-function mutations in the Drosophila spastin gene produce larval neuromuscular junction (NMJ) phenotypes. NMJ synaptic boutons in spastin mutants are more numerous and more clustered than in wild-type, and transmitter release is impaired. spastin-null adult flies have severe movement defects. They do not fly or jump, they climb poorly, and they have short lifespans. spastin hypomorphs have weaker behavioral phenotypes. Overexpression of Spastin erases the muscle microtubule network. This gain-of-function phenotype is consistent with the hypothesis that Spastin has microtubule-severing activity, and implies that spastin loss-of-function mutants should have an increased number of microtubules. Surprisingly, however, we observed the opposite phenotype: in spastin-null mutants, there are fewer microtubule bundles within the NMJ, especially in its distal boutons. The Drosophila NMJ is a glutamatergic synapse that resembles excitatory synapses in the mammalian spinal cord, so the reduction of organized presynaptic microtubules that we observe in spastin mutants may be relevant to an understanding of human Spastin's role in maintenance of axon terminals in the spinal cord.

Adenosine Triphosphatases↗
PubMed2003

The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis.

In a genetic screen for mutations that restrict cell growth and organ size, we identified a new tumor suppressor gene, dMST, which encodes the Drosophila homolog of the mammalian Ste20 kinase family members MST1 and MST2. Loss-of-function mutations in dMST result in overgrown tissues containing more cells of normal size. dMST mutant cells exhibit elevated levels of Cyclin E and DIAP1, increased cell growth and proliferation, and impaired apoptosis. dMST forms a complex with Sav and Wts, two tumor suppressors also implicated in regulating both cell proliferation and apoptosis, suggesting that they act in common pathways.

Amino Acid Sequence↗
PubMed1996

Temperature-sensitive mutants of p16CDKN2 associated with familial melanoma.

Altered expression or function of the p16CDKN2 tumor suppressor gene on chromosome 9p21 occurs in a wide range of human tumors, and mutations in the gene have been shown to segregate with familial predisposition to malignant melanoma. We have used a variety of assays to examine the functional properties of tumor-associated alleles, including eight premature termination mutants, eight missense mutants, and three isoforms of p16 initiated at different amino-terminal methionine codons. The amino- and carboxy-terminal domains of the protein, outside the ankyrin-like repeats, appeared to be dispensable, but the majority of the premature termination mutations led to loss of function. Of the missense mutations tested, four displayed clear loss of function whereas two behaved like the wild type under all conditions tested. The remaining two mutations, a G-to-W mutation at position 101 (Gl01W) and V126D, both of which are associated with familial melanoma, were found to be temperature sensitive for binding to Cdk4 and Cdk6 in vitro, for inhibiting cyclin D1-Cdk4 in a reconstituted pRb-kinase assay, and for increasing the proportion of G1-phase cells following transfection. These findings clarify previous disparities and argue strongly that p16CDKN2 is a bona fide tumor suppressor associated with familial melanoma.

Bone Neoplasms↗
PubMed1994

The sevenless signalling cassette mediates Drosophila EGF receptor function during epidermal development.

In Drosophila, Drk, an SH2 adaptor protein, Sos, a putative activator of Ras1, Ras1, raf and rolled/MAP kinase have been shown to be required for signalling from the sevenless and the torso receptor tyrosine kinase. From these studies, it was unclear whether these components act in a single linear pathway as suggested by the genetic analysis or whether different components serve to integrate different signals. We have analyzed the effects of removing each of these components during the development of the adult epidermal structures by generating clones of homozygous mutant cells in a heterozygous background. Mutations in each of these signalling components produce a very similar set of phenotypes. These phenotypes resemble those caused by loss-of-function mutations in the Drosophila EGF receptor homolog (DER). It appears that these components form a signalling cassette, which mediates all aspects of DER signalling but that is not required for other signalling processes during epidermal development.

Animals↗
PubMed2026

Recurrent reversible mutations at gaf1 driving metastable TORC1 inhibitor resistance in fission yeast.

Metastable phenotypic inheritance is often attributed to epigenetic mechanisms, but reversible genetic alterations can produce similar instability. Here, we investigated the basis of unstable resistance to TORC1 inhibitor (rapamycin plus caffeine) in Schizosaccharomyces pombe. Six independent, metastable resistant mutants were isolated. Genetic mapping positioned the causal lesion to a single Mendelian locus, which sequencing identified as gaf1, encoding a GATA transcription factor and a key negative regulator of growth downstream of TORC1. In each mutant, distinct loss-of-function mutations (insertions, deletions, or point mutations) were found in gaf1 in the resistant state, and these mutations precisely reverted to the wild-type sequence upon loss of resistance. Restoring the wild-type gaf1 allele abolished resistance, indicating that reversible genetic disruption of gaf1 is both necessary and sufficient for the metastable phenotype. Furthermore, strong resistance in several strains from a genome-wide deletion library was due to secondary, inactivating mutations in gaf1, underscoring its role as a recurrent adaptive target under rapamycin plus caffeine treatment. Mechanistically, gaf1 inactivation established a distinct basal transcriptome and pronounced derepression of translation and metabolic programs upon drug treatment. While rapamycin plus caffeine triggered extensive chromatin remodeling and H3K9 methylation contributed partially to resistance, these epigenetic changes were most consistent with a downstream modifying layer. Our study shows that metastable drug resistance in fission yeast is predominantly associated with recurrent, reversible genetic inactivation of the central transcriptional regulator gaf1, demonstrating how rapidly reversible genetic switches can drive adaptive evolution.IMPORTANCEDistinguishing between genetic and epigenetic inheritance is fundamental to understanding how cells adapt to environmental stress. In the fission yeast Schizosaccharomyces pombe, rapid and reversible drug resistance is often assumed to be driven by epigenetic switches that change gene activity without altering DNA. However, our study reveals that this instability can be caused by physical mutations in a single gene, gaf1, which acts as a genetic toggle. These mutations appear under drug pressure and precisely revert to the original sequence when the drug is removed. We also demonstrate that these spontaneous mutations can contaminate standard laboratory yeast collections, leading to potential misinterpretation of experimental data. These findings broaden our understanding of unstable inheritance and show that DNA sequences can be far more dynamic than previously recognized during rapid evolution and the development of drug resistance.

TORC1 signaling↗
PubMed1999

Identification of eleven novel tumor-associated E-cadherin mutations. Mutations in brief no. 215. Online.

The cell adhesion molecule E-cadherin (CDH1; MIM# 192090) has been implicated in numerous cellular functions, ranging from controlling morphogenesis to suppressing tumor invasion. We describe 11 previously unreported somatic E-cadherin mutations in two subgroups of gastric and breast cancer showing markedly reduced homophilic cell-to-cell interactions. Using reverse transcription-polymerase chain reaction (RT-PCR) and direct sequencing of the entire coding region 5 mutations were detected in diffuse-type gastric cancer specimens. The sequence alterations include 3 missense mutations affecting exons 3, 10, and 12. Furthermore, two in-frame deletions were identified removing 63 and 9 base pairs from exon 4 and 5, respectively. In invasive Lobular breast cancer 6 E-cadherin mutations were detected after RT-PCR amplification and direct sequencing or using single strand conformation polymorphism (SSCP) analysis followed by sequencing. In addition to two nonsense mutations affecting exon 2, four out-of-frame deletions removing 115 base pairs (entire exon 2), 224 base pairs (entire exon 3), 8 base pairs from exon 12 or 1 base pair from exon 13 were seen. Our report confirms the general principle that in diffuse-type gastric cancer E-cadherin mutations result in structurally altered proteins with possible reduced adhesive functions whereas in invasive lobular breast carcinomas complete loss-of-function mutations are characteristic.

Breast Neoplasms↗
PubMed2006

A compound heterozygote harboring novel and recurrent DTDST mutations with intermediate phenotype between atelosteogenesis type II and diastrophic dysplasia.

Diastrophic dysplasia sulfate transporter (DTDST) is a sulfate transporter required for the synthesis of sulfated proteoglycans in the cartilage. Over 30 mutations have been described in the DTDST gene, which result in a continuous clinical spectrum of recessively inherited chondrodysplasias, including, in order of increasing severity, a recessive form of multiple epiphyseal dysplasia (rMED), diastrophic dysplasia (DTD), atelosteogenesis type II (AO-II) and achondrogenesis 1B (ACG-1B). Correlation between disease severity and residual sulfate transport activity has been reported. Here we report a patient with DTDST mutations, whose manifestations fell in a range between AO-II and DTD. The patient was a compound heterozygote for the recurrent c.835C>T (p.R279W) and novel c.1987G>A (p.G663R) mutations. Immunocytochemical analysis in HEK293 cells showed that the p.G663R mutation was localized within the cytoplasm, and not to the cell membrane, suggesting p.G663R is a loss-of-function mutation. Our case supports the previously described correlation between the severity of the phenotype and the putative level of residual transport function.

Abnormalities, Multiple↗
PubMed1997

Genetic depletion reveals an essential role for an SR protein splicing factor in vertebrate cells.

SR proteins are essential for the splicing of messenger RNA precursors in vitro, where they also alter splice site selection in a concentration-dependent manner. Although experiments involving overexpression or dominant mutations have confirmed that these proteins can influence RNA processing decisions in vivo, similar results with loss-of-function mutations have been lacking. Now, a system for genetic depletion of the chicken B cell line DT40 has revealed that the SR protein ASF/SF2 (alternative splicing factor/splicing factor 2) is essential for viability in these cells(1). This study opens the way for a complete functional dissection of this protein, and other SR proteins, in vivo.

Amino Acid Sequence↗
PubMed1997

The human homolog of the rodent immediate early response genes, PC4 and TIS7, resides in the lung cancer tumor suppressor gene region on chromosome 3p21.

Recently, human chromosome band 3p21.3 was shown to undergo overlapping homozygous deletions in several small cell lung cancer lines further defining a putative tumor suppressor gene(s) region. We report the cloning and mutational analysis of a novel human gene, SKMc15, from the commonly homozygously deleted region in three small cell lung cancer lines (NCI-H1450, NCI-H740, GLC20). It has 11 exons ranging in size from 50 to 541 bp with an open reading frame of 442 amino acids. The gene covers 7 to 10 kb of genomic DNA; the message of 1.8 to 2 kb is expressed in all analyzed fetal and adult human and mouse tissues including heart, brain, placenta, lung liver, skeletal muscle, kidney, testis and pancreas and in small cell and non-small cell cancer lines. The intron/exon boundaries were used to analyze the gene for mutations by exon PCR-SSCP sequencing in 60 small cell lung cancer cell lines. No loss-of-function mutations were detected. The cDNA sequence has high homology, 75% at the protein level, to the rat early response gene PC4 and its murine homolog TIS7. In addition, the known partial sequence of the putative mouse interferon beta2 (64 amino acids) gene is highly conserved in PC4/TIS7 (94%) and in SKMc15 (83%) at the amino acid level. The sequence TAAAT, which is thought to be involved in mRNA degradation, is present in the 3' UTR of SKMc15 and in the 3' UTR of PC4 and TIS7 genes.

Amino Acid Sequence↗
PubMed2005

Methylation status of EXT1 and EXT2 promoters and two mutations of EXT2 in chondrosarcoma.

Germline mutation and functional loss of EXT1 or EXT2 are commonly found in multiple osteochondromas and predispose to the development of chondrosarcoma. Mutations of EXT1 and EXT2 have rarely been detected in sporadic secondary chondrosarcomas from osteochondroma; these frequently display loss of heterozygosity at the EXT1 and EXT2 loci, but primary chondrosarcomas typically do not. To evaluate promoter methylation (which is an epigenetic gene silencing mechanism) of EXT1 and EXT2, we performed methylation-specific polymerase chain reaction (PCR) for 20 chondrosarcoma cases (12 primary, 3 secondary to osteochondroma, 2 secondary to enchondromatosis, 2 extraskeletal ordinary, and 1 clear cell) and in five cell lines. In addition, mutation analysis of the EXT1 and EXT2 coding regions was performed using PCR-single-strand conformation polymorphism and sequencing analysis for 12 of the 20 chondrosarcoma cases (8 primary, 1 secondary to enchondromatosis, 1 secondary to osteochondroma, and 2 extraskeletal ordinary) and five cell lines. Promoter methylation of EXT1 and EXT2 was not detected in any of the cases, and both EXT1 and EXT2 were expressed in all cell lines. Two missense mutations in EXT2 (D227E and R299H) were detected among the chondrosarcoma cases. When considering tumor development in primary chondrosarcoma, we should include mutations in EXT2, along with the status of other members of the EXT gene family.

5' Untranslated Regions↗
PubMed2002

Frequent Fas gene mutations in testicular germ cell tumors.

The Fas (Apo-1/CD95)/Fas ligand (L) system is involved in cell death signaling, and has been suggested to be important for the regulation of germ cell apoptosis in the testis. Mutations of the Fas gene may result in accumulation of germ cells and thus might contribute to testicular carcinogenesis. The open reading frame of Fas cDNA was examined in 24 cases of testicular germ cell tumors (TGCTs), comprised of 19 pure histological type (15 seminomas, 3 embryonal carcinomas, 1 immature teratoma) and 5 mixed-type tumors. Mutations of the Fas gene were found in nine (37.5%) of these cases. Each lesion with a homogeneous histological picture was selectively microdissected using a laser capture microdissection method: samples consisted of 18 lesions from seminomas, 7 embryonal carcinomas, 4 immature teratomas, 2 choriocarcinomas, and 1 from a yolk sac tumor. Microdissected genomic DNA was examined to determine which mutations were derived from which kind of histological lesion. Eleven mutations were detected in 10 TGCT lesions from nine cases, but none were found in benign lesions. All were point mutations, and eight missense mutations occurred in exon 9 encoding the core protein of the death domain essential for apoptotic signal transduction. Three were silent mutations. Mutations were found in the seminoma (27.8%) and embryonal carcinoma lesions (62.5%), but none were found in the one yolk sac tumor, two choriocarcinomas, or four immature teratoma lesions. Each seminoma and embryonal carcinoma lesion found in the same case had a different type of Fas mutation from the others. Mouse T-cell lymphoma cells transfected with missense mutated genes were resistant to apoptosis induced by anti-Fas antibody, indicating these to be loss-of-function mutations. These findings suggested a role of Fas gene mutations in the pathogenesis of TGCTs.

Adult↗
PubMed2004

The DeltaF508 mutation results in loss of CFTR function and mature protein in native human colon.

BACKGROUND AND AIMS: Deletion of the codon for phenylalanine at position 508 (DeltaF508) is the most frequent disease-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In heterologous cells, defective processing of the DeltaF508 protein results in endoplasmic reticulum retention, proteolytic degradation, and absence of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent plasma membrane Cl(-) conductance. However, data with respect to the processing block of DeltaF508 protein in native epithelia are limited and conflicting. METHODS: To characterize both the fate and function of DeltaF508 protein in a native epithelium, we measured CFTR-mediated Cl(-) secretion, localization of the CFTR protein, and CFTR maturation in rectal biopsy specimens from normal individuals and DeltaF508 homozygous patients with cystic fibrosis (CF). RESULTS: Ussing chamber studies showed that cAMP-dependent and cholinergic Cl(-) secretion was absent from rectal tissues freshly excised from DeltaF508 homozygous patients with CF. By immunohistochemistry, we detected wild-type but not DeltaF508 CFTR at the luminal membrane of crypt colonocytes. By sequential immunoprecipitation and immunoblotting analyses, mature CFTR protein was detected in normal but not in DeltaF508 homozygous tissues. CONCLUSIONS: Collectively, these data show that there is insufficient maturation and transport of DeltaF508 CFTR from the endoplasmic reticulum to the apical membrane to support CFTR-mediated Cl(-) secretion in the CF colon.

Adolescent↗
PubMed2001

A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome, characterized primarily by multiple tumors in the parathyroid glands, endocrine pancreas, and anterior pituitary. Other tumors, including gastrinoma, carcinoid, adrenal cortical tumors, angiofibroma, collagenoma, and lipoma, also occur in some patients. Individuals with MEN1 almost always have loss-of-function mutations in the MEN1 gene on chromosome 11, and endocrine tumors arising in these patients usually show somatic loss of the remaining wild-type allele. To examine the role of MEN1 in tumor formation, a mouse model was generated through homologous recombination of the mouse homolog Men1. Homozygous mice die in utero at embryonic days 11.5-12.5, whereas heterozygous mice develop features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets show a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas are also frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary are seen by 16 months. All of the tumors tested to date show loss of the wild-type Men1 allele, further supporting its role as a tumor suppressor gene.

Adenoma↗
PubMed1995

Tyrosines outside the kinase core and dimerization are required for the mitogenic activity of RET/ptc2.

Defects in the c-ret proto-oncogene, a member of the protein tyrosine kinase receptor family, have recently been linked to two types of genetic syndromes, Hirschsprung's disease and the multiple endocrine neoplasia family of inherited cancers. RET/ptc2 is the product of a papillary thyroid carcinoma translocation event between the genes coding for c-ret and the type I alpha regulatory subunit of protein kinase A (RI alpha) (Lanzi, C., Borrello, M., Bongarzone, I., Migliazza, A., Fusco, A., Grieco, M., Santoro, M., Gambetta, R., Zunino, F., Della Porta, G., and Pierotti, M. (1992) Oncogene 7, 2189-2194). The resulting 596-residue protein contains the first two-thirds of RI alpha and the entire tyrosine kinase domain of c-ret (RETtk). An in vivo assay of growth stimulatory effects was developed, which consisted of microinjecting a RET/ptc2 expression plasmid into the nuclei of 10T1/2 mouse fibroblasts and observing the incorporation of 5-bromodeoxyuridine. This assay was used to determine that only the dimerization domain of RI alpha fused to RETtk is required for RET/ptc2's mitogenic activity. In addition, all of the reported Hirschsprung's disease point mutations in the RETtk (S289P, R421Q, and R496G) inactivate RET/ptc2 in our assay, confirming that these are loss of function mutations. Two tyrosines outside the conserved kinase core were also identified that are essential for full mitogenic activity of RET/ptc2. These two tyrosines, Tyr-350 and Tyr-586, are potential sites for Src homology 2 and phosphotyrosine binding domain interactions.

Animals↗
PubMed2002

Analysis of Fas gene mutations on laser capture microdissected specimens from renal cell carcinoma.

Renal cell carcinoma (RCC) expresses Fas antigen on the cell surface, and thus could be sensitive to apoptosis induced by the binding of Fas ligand. Fas gene mutations might be involved in the development of RCC. Fas gene mutations were examined in genomic DNA extracted from RCC lesions. With use of laser capture methods, one RCC and one non-neoplastic lesion per case were microdissected from 15 patients with RCC. Polymerase chain reaction-amplified products were directly sequenced. Loss of heterozygosity (LOH) was examined at four sites of known polymorphism. Mutations of the Fas gene were detected in 3 RCC lesions from 3 (20%) of 15 cases. All mutations were point mutations, 2 missense and one silent, in exons 7 and 9. Non-neoplastic tissues never showed Fas gene mutations. Nine of 15 cases (60.0%) were heterozygous for one or more sites of the known biallelic polymorphisms, i.e., at nucleotides -1377, -670, 416, and 836. Two of these 9 cases showed LOH at promoter region -670. Mouse T-cell lymphoma cells transfected with missense mutated genes were resistant to apoptosis induced by anti-Fas antibody, indicating these to be loss-of-function mutations. The results of the present study suggest that Fas gene mutations play a role in the pathogenesis of RCC.

Adult↗
PubMed2001

Mutations in the Na-Cl cotransporter reduce blood pressure in humans.

The relationship between salt homeostasis and blood pressure has remained difficult to establish from epidemiological studies of the general population. Recently, mendelian forms of hypertension have demonstrated that mutations that increase renal salt balance lead to higher blood pressure, suggesting that mutations that decrease the net salt balance might have the converse effect. Gitelman's syndrome, caused by loss of function mutations in the Na-Cl cotransporter of the distal convoluted tubule (NCCT), features inherited hypokalemic alkalosis with so-called "normal" blood pressure. We hypothesized that the mild salt wasting of Gitelman's syndrome results in reduced blood pressure and protection from hypertension. We have formally addressed this question through the study of 199 members of a large Amish kindred with Gitelman's syndrome. Through genetic testing, family members were identified as inheriting 0 (n=60), 1 (n=113), or 2 (n=26) mutations in NCCT, permitting an unbiased assessment of the clinical consequences of inheriting these mutations by comparison of the phenotypes of relatives with contrasting genotypes. The results demonstrate high penetrance of hypokalemic alkalosis, hypomagnesemia, and hypocalciuria in patients inheriting 2 mutant NCCT alleles. In addition, the NCCT genotype was a significant predictor of blood pressure, with homozygous mutant family members having significantly lower age- and gender-adjusted systolic and diastolic blood pressures than those of their wild-type relatives. Moreover, both homozygote and heterozygote subjects had significantly higher 24-hour urinary Na(+) than did wild-type subjects, reflecting a self-selected higher salt intake. Finally, heterozygous children, but not adults, had significantly lower blood pressures than those of the wild-type relatives. These findings provide formal demonstration that inherited mutations that impair renal salt handling lower blood pressure in humans.

Alkalosis↗