Abl Oncogene Research Articles

Amplification of 9q34 in childhood adrenocortical tumors: a specific feature unrelated to ethnic origin or living conditions.

Adrenocortical tumors (ACT) in children under 15 years of age exhibit some clinical and biological features distinct from ACT in adults. Cell proliferation, hypertrophy and cell death in adrenal cortex during the last months of gestation and the immediate postnatal period seem to be critical for the origin of ACT in children. Studies with large numbers of patients with childhood ACT have indicated a median age at diagnosis of about 4 years. In our institution, the median age was 3 years and 5 months, while the median age for first signs and symptoms was 2 years and 5 months (N = 72). Using the comparative genomic hybridization technique, we have reported a high frequency of 9q34 amplification in adenomas and carcinomas. This finding has been confirmed more recently by investigators in England. The lower socioeconomic status, the distinctive ethnic groups and all the regional differences in Southern Brazil in relation to patients in England indicate that these differences are not important to determine 9q34 amplification. Candidate amplified genes mapped to this locus are currently being investigated and Southern blot results obtained so far have discarded amplification of the abl oncogene. Amplification of 9q34 has not been found to be related to tumor size, staging, or malignant histopathological features, nor does it seem to be responsible for the higher incidence of ACT observed in Southern Brazil, but could be related to an ACT from embryonic origin.

Transposition of Duplicated Chromosomal Segment Involving Fused BCR-ABL Gene or ABL Oncogene Alone in Chronic Myelocytic Leukemia and Ph Chromosome-Positive Acute Leukemia with Complex Karyotypes

Thirty-six patients with chronic myelocytic leukemia (CML) in the blastic phase were examined by fluorescence in situ hybridization to clarify the mechanisms of progression of the disease. Two of 19 CML patients in the blastic phase (10.5%) had an extra fused BCR-ABL gene on structurally complex chromosome aberrations in addition to the Ph chromosome. Another patient had an extra ABL oncogene on the end of a deleted chromosome, resulting in three copies of the ABL oncogene. These three patients showed additional chromosome aberrations, such as der(12), der(15), and der(18), which differ from the standard karyotypic evolution in the blastic phase. Amplification of the fused BCR-ABL gene or the ABL oncogene seemed to be induced by transposition. These segmental transpositions suggest that these regions have high genetic instability possibly leading to blastic transformation.

Bcr-Abl with an SH3 deletion retains the ability To induce a myeloproliferative disease in mice, yet c-Abl activated by an SH3 deletion induces only lymphoid malignancy.

The bcr-abl oncogene plays a critical role in the pathogenesis of chronic myelogenous leukemia (CML). The fusion of Bcr sequences to Abl constitutively activates the Abl protein tyrosine kinase. We have recently shown that expression of Bcr-Abl in bone marrow cells by retroviral transduction efficiently induces in mice a myeloproliferative disease resembling human CML and that Abl kinase activity is essential for Bcr-Abl to induce a CML-like myeloproliferative disease. However, it is not known if activation of the Abl kinase alone is sufficient to induce a myeloproliferative disease. In this study, we examined the role of the Abl SH3 domain of Bcr-Abl in induction of myeloproliferative disease and tested whether c-Abl activated by SH3 deletion can induce a CML-like disease. We found that Bcr-Abl with an Abl SH3 deletion still induced a CML-like disease in mice. In contrast, c-Abl activated by SH3 deletion induced only lymphoid malignancies in mice and did not stimulate the growth of myeloid colonies from 5-fluorouracil-treated bone marrow cells in vitro. These results indicate that Bcr sequences in Bcr-Abl play additional roles in inducing myeloproliferative disease beyond simply activating the Abl kinase domain and that functions of the Abl SH3 domain are either not required or redundant in Bcr-Abl-induced myeloproliferative disease. The results also suggest that the type of hematological neoplasm induced by an abl oncogene is influenced not only by what type of hematopoietic cells the oncogene is targeted into but also by the intrinsic oncogenic properties of the particular abl oncogene. In addition, we found that DeltaSH3 c-Abl induced less activation of Akt and STAT5 than did Bcr-Abl, suggesting that activation of these pathways plays a critical role in inducing a CML-like disease.

ABL amplification in a patient with lymphoid blast crisis of chronic myelogenous leukaemia

Although chronic phase myelogenous leukaemia (CML) is characterised by the Philadelphia (Ph) chromosome leading to a fusion of the BCR and ABL genes, additional genetic alterations involved in blast crisis are poorly understood. We report an at least 15-fold amplification of the ABL oncogene in a 29-year-old male patient with a variant Ph-positive t(19;22)(p13;q11.2) CML who presented in lymphoid blast crisis. Our finding suggests that an amplification of the ABL oncogene might play a part in the appearance of an aggressive phenotype in some cases of CML.

Abl protein kinase abrogates the response of multipotent haemopoietic cells to the growth inhibitor macrophage inflammatory protein-1 alpha.

The clonogenic cells of chronic myeloid leukaemia (CML), unlike normal haemopoietic progenitor cells, are resistant to the growth inhibitory effects of the chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha). CML is also relatively resistant to chemotherapy and the disease is difficult to cure using conventional therapeutic routes. CML is associated with increased abl oncogene protein tyrosine kinase (PTK) activity. Here, we have tested the hypothesis that these aberrant responses to MIP-1alpha and the relative resistance to chemotherapy are directly related to this increased abl PTK activity in primitive haemopoietic cells. To do this we have expressed a temperature sensitive abl PTK in a growth factor dependent, multipotent stem cell line (FDCP-Mix) in which growth is normally suppressed by MIP-1alpha. In FDCP-Mix cells expressing the ts v-abl PTK and grown at the restrictive temperature for PTK activity the cells were relatively sensitive to cytotoxic agents such as cytosine arabinoside and 5-fluorouracil but MIP-1alpha could induce growth inhibition and confer some degree of protection from these agents. At the permissive temperature for abl PTK, the cells were relatively resistant to cytotoxic drugs and MIP-1alpha treatment neither induced growth inhibition nor protected the cells from cytotoxic drug induced cell death. This lack of response to MIP-1alpha was not due to receptor down modulation as neither the affinity nor the number of 125I-MIP-1alpha binding sites was altered by activating Abl PTK. However, MIP-1alpha mediated increases in cytosolic Ca2+ levels were abrogated by switching cells to the permissive temperature for Abl PTK activity. These data suggest that the relative resistance of CML progenitor cells to therapeutic drugs and the lack of response to MIP-1alpha occurs as a direct consequence of abl PTK activity and involves desensitisation of signal transduction events stimulated by MIP-1alpha receptors. Thus one contributory mechanism to transformation of primitive haemopoietic cells is abrogation of response to a growth inhibitor.

Segmental Jumping Translocation in Leukemia and Lymphoma with a Highly Complex Karyotype

In order to identify the oncogene associated with malignant transformation 141 leukemia and malignant lymphoma patients were studied by FISH. Specific chromosome regions were translocated onto structurally abnormal chromosomes, resulting in partial tri-, tetra-, or pentasomy of these regions. We designated this type of chromosomal translocation as a “segmental jumping translocation (SJT)”. These SJTs were found in several chromosomal regions such as 8q24, 9q34, 11q13, 11q23, 13q14, 14q24-q32, 21q22 and 22q11. The SJT at 9q34, which involved the ABL oncogene, was found in three of nine secondary leukemia patients who were treated with anticancer drugs and radiation. Non-Hodgkin's lymphoma and acute myeloid leukemia (AML) patients had 3–7 copies of SJT at 11q13 or 11q23. SJT at 14q32 and 21q22 were predominantly detected in the acute type of adult T-cell leukemia (8 of 27 patients) and in AML (5 of 17 patients). The size of the SJT regions varied among the patients. The overlapping region within the SJT could involve oncogene(s) associated with transformation to the advanced stage in leukemia and lymphoma patients. The SJT provides evidence of a new mechanism for gene amplification and formation of unidentified marker chromosomes in the advanced disease stage.

Identification and Characterization of the Human Homologue of SH3BP2, an SH3 Binding Domain Protein within a Common Region of Deletion at 4p16.3 Involved in Bladder Cancer

In a search for candidate tumor suppressor genes within a 30-kb common region of deletion previously identified in bladder cancer cell lines, we isolated a 2.4-kb cDNA clone comprising 13 exons that spanned approximately 16 kb of genomic DNA. Mutation analysis was carried out by single-strand conformation polymorphism analysis on DNA from 12 bladder carcinoma cell lines and 26 bladder tumors with LOH on chromosome 4p. Direct sequencing of the transcript in 4 bladder carcinoma cell lines with deletions in this region was also carried out. Two polymorphisms in exons 2 and 5 were identified, but no tumor-specific mutations were found. Sequence analysis identified a high degree of homology with the mouse sh3bp2 gene, which is abl-binding, suggesting that this gene is the human homologue. The predicted amino acid sequence of the putative gene product contains a Src homology 2 domain, a Src homology 3 binding domain, and a pleckstrin homology domain, suggesting a possible role in signal transduction. No evidence was found to indicate that SH3BP2 is the tumor suppressor gene at 4p16.3 involved in bladder cancer. However, this study has identified an interesting human gene that is a potential negative regulator of the abl oncogene.

Tyrosine phosphorylation of p120cbl in BCR/abl transformed hematopoietic cells mediates enhanced association with phosphatidylinositol 3-kinase.

Increased tyrosine kinase activity of abl oncogene in Philadelphia chromosome positive-leukemic cells leads to activation of p21ras and phosphatidylinositol 3'-kinase (PI 3-Kinase). The mechanism of activation of these signaling pathways is not understood, but numerous studies have focused on the identification and characterization of downstream substrates of BCR/abl tyrosine kinase as potential mediators of oncogenic signaling. It was recently found that the 120 kDa protein product of the c-cbl proto-oncogene is highly tyrosine phosphorylated and associates with BCR/abl in transformed hematopoietic cells. We have characterized further cbl's involvement in BCR/abl mediated tumorigenesis using growth factor independent BCR/abl transformed BaF3 cells. Our experiments show that, in contrast to other cell types, the in vivo interaction of cbl with GRB2 and p85 is significantly enhanced in BCR/abl transformed BaF3 cells and that tyrosine phosphorylation of cbl leads to a direct interaction with GRB2, p85 and abl SH2 domains. A 14-fold increase in cbl associated PI 3-kinase activity in BCR/abl transformed cells suggests that the binding of p85 SH2 domains to tyrosine phosphorylated cbl may contribute to PI 3-kinase activation. Domain analysis studies indicate that both SH3 domains of GRB2 bind to the proline rich region of cbl in quiescent BaF3 cells, whereas GRB2 SH2 domain interacts with a non-contiguous sequence of cbl in transformed cells. Although the interaction of cbl with GRB2 in transformed cells was facilitated by binding of GRB2 to BCR/abl, phosphorylation of cbl and its interaction with p190 BCR/abl remained unaltered in BaF3 cells transformed by p190Y177F BCR/abl mutant which is unable to bind GRB2. The current information and the data presented here suggest that, although cbl lacks src homology domains, it represents a novel intermediate protein which, by interaction with key SH-containing adaptor proteins, may participate in regulation of the Ras and PI 3-kinase pathways in BCR/abl transformed hematopoietic cells.

Frequent Jumping Translocations of Chromosomal Segments Involving the ABL Oncogene Alone or in Combination With CD3-MLL Genes in Secondary Leukemias

AbstractSeven secondary leukemia patients were treated for solid tumors or malignant lymphoma with anticancer drugs or radiation. We studied bone marrow samples from these patients by fluorescence in situ hybridization (FISH). Of the seven patients, three had increased signals for the ABL oncogene (9q34) on interphase nuclei and at metaphase. One of the three patients also had four signals for the CD3 (MLL) region (11q23). Whole painting probes revealed that these chromosomal regions were translocated onto structurally abnormal chromosomes, resulting in partial tri-, tetra- or penta-somy of these regions. We called this type of translocation “segmental jumping translocation (SJT).” SJT of the ABL oncogene was not detected in samples from 15 patients with de novo acute myelocytic leukemia (AML), 12 with myelodysplastic syndrome (MDS), or 20 with chronic myelocytic leukemia (CML) at the chronic phase. Furthermore, monosomy 7 was also found in the patients with the gene amplification. These results indicate that SJT of ABL and/or CD3 (MLL) genes is associated with the leukemogenesis of secondary leukemia. The SJT may be one mechanism of gene amplification.

An Activating Mutation in the ATP Binding Site of the ABL Kinase Domain

A number of structural alterations have been shown to activate the leukemogenic potential of the ABL oncogene, but there is little understanding of the regulatory mechanisms that are subverted by such changes. We have used directed mutagenesis to examine a potential regulatory motif in cABL, which could directly influence ABL tyrosine kinase activity. A tyrosine to phenylalanine substitution within the ATP binding fold of the ABL kinase domain is sufficient to activate cABL enzymatic activity, and the mutant protein will alleviate growth factor dependence when expressed in the BA/F3 cell line. This growth promotion is dependent upon the structure of the amino terminus of the protein, and the ABL mutation will cooperate with certain BCR sequences in BCR/ABL fusion proteins to deregulate ABL kinase activity.

ChemInform Abstract: Isolation from Streptomyces of a Novel Naphthoquinone Compound, Naphthablin, that Inhibits Abl Oncogene Functions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Isolation from Streptomyces of a novel naphthoquinone compound, naphthablin, that inhibits Abl oncogene functions.

In the course of our screening for inhibitors of abl oncogene function, a culture filtrate of Streptomyces aculeolatus, induced normal flat morphology in v-abl-expressing NIH3T3 cells. The active substance was isolated through ethyl acetate extraction, silica gel column chromatography, and reverse-phase HPLC. Mass and NMR spectroscopy including HMBC revealed that it had a novel naphthoquinone structure with a monoterpene, and we named it "naphthablin". Naphthablin inhibited Abl-induced morphological transformation in v-ablts-NIH3T3 cells at around 30 micrograms/ml, and specifically inhibited RNA synthesis.

Transformation, growth rate, and the heme biosynthetic pathway in V-abl-transfected fibroblasts.

The relationship between growth rate and various parameters of the heme biosynthetic pathway was studied in two cell lines of rat fibroblasts (REabl-1 and REabl-3) transfected with v-abl oncogene, coded by the Abelson murine leukemia virus, and subjected to glucocorticoid dependent transformation. In the REabl-1 cell line, whose growth rate was only slightly affected by dexamethasone (DX), almost no change was noticed either in heme content or in the enzymatic activities of aminolevulinate synthase (ALAS), porphobilinogen deaminase (PBGD), and ferrochelatase (FC) in the presence of various concentrations of DX. In the REabl-3 cell line, exhibiting a growth rate highly sensitive to DX, a significant reduction in intracellular heme concomitantly with decreases in ALAS and FC activities and a threefold increase in PBGD were noted. The fact that incubation with 10(-5)M hemin did not result in a decrease in ALAS activity raised the possibility that REabl cells lack a negative feedback control mechanism. The relationships between transformation, growth rate, and heme biosynthetic pathway are discussed.

Identification of Philadelphia-negative granulocyte-macrophage colony- forming units generated by stroma-adherent cells from chronic myelogenous leukemia patients

Chronic myelogenous leukemia (CML) is a clonal disorder of the hematopoietic stem cell characterized by the coexistence of Philadelphia-negative (Ph-) with Ph+ progenitors. CML progenitor cells have been shown to be defective in adherence to marrow stroma. The present study investigated at the cytogenetic level marrow-derived CML clonogenic cells generated from the stroma-adherent cell fraction. On direct cytogenetic analysis, the overall mean (+/- SEM) percentage of Ph- metaphases was 3% +/- 1%. Mononuclear marrow cells from CML patients (n = 18) were incubated with mafosfamide (100 micrograms/mL) or control medium, seeded onto marrow stromal layers and allowed to adhere (2 hours, 37 degrees C). After a short-term (3-day) liquid culture, the cells were harvested, incorporated in methyl-cellulose, and individual colonies were analyzed by single colony karyotyping. The mean (+/- SEM) percentage of Ph- colonies generated from the stroma- adherent fraction was 35% +/- 6%. As compared with marrow colony- forming unit granulocyte-macrophage plated before any manipulation, the mean (+/- SEM) percentage of Ph- clones was significantly increased by stroma adherence (35% +/- 6% v 15% +/- 4%, P < or = .005) and mafosfamide (100 micrograms/mL) incubation of marrow cells before stroma adherence (58% +/- 9% v 35% +/- 6%, P < or = .005). An additive effect was observed by combining mafosfamide treatment and stroma adherence. Single-colony transfer experiments showed that 50% +/- 4% stroma-adherent and 70% +/- 4% stroma-adherent mafosfamide-treated progenitors gave rise to secondary colonies. To further characterize the stroma-adherent fraction, experiments were performed in which CD34+ marrow cells were used. The mean (+/- SEM) output of progenitors generated by 10,000 CD34+, stroma-adherent cells was 888 +/- 188 and 570 +/- 258 for untreated and mafosfamide-treated cells, respectively. Individual colonies were analyzed by single-colony karyotyping and fluorescent in situ hybridization using a biotinylated cosmid DNA probe that hybridize to abl oncogene. The CD34+, stroma-adherent fraction contained 38% +/- 14% (untreated) and 56% +/- 18% (mafosfamide-treated) (P < or = .025) Ph- progenitors. In conclusion, the present data show the possibility to select Ph- clones that (1) have a maintained capability of stroma adherence, (2) are mafosfamide resistant, (3) are derived from the CD34+ fraction, and (4) have high-replating potential.

Identification of Philadelphia-Negative Granulocyte-Macrophage Colony-Forming Units Generated by Stroma-Adherent Cells From Chronic Myelogenous Leukemia Patients

AbstractChronic myelogenous leukemia (CML) is a clonal disorder of the hematopoietic stem cell characterized by the coexistence of Philadelphia-negative (Ph-) with Ph+ progenitors. CML progenitor cells have been shown to be defective in adherence to marrow stroma. The present study investigated at the cytogenetic level marrow-derived CML clono-genic cells generated from the stroma-adherent cell fraction. On direct cytogenetic analysis, the overall mean (± SEM) percentage of Ph- metaphases was 3% ± 1 %. Mononuclear marrow cells from CML patients (n = 18) were incubated with mafosfamide (100 μg/mL) or control medium, seeded onto marrow stromal layers and allowed to adhere (2 hours, 37°C). After a short-term (3-day) liquid culture, the cells were harvested, incorporated in methyl-cellulose, and individual colonies were analyzed by single colony karyotyping. The mean (± SEM) percentage of Ph-colonies generated from the stroma-adherent fraction was 35% ± 6%. As compared with marrow colony-forming unit granulocyte-macrophage plated before any manipulation, the mean (± SEM) percentage of Ph- clones was significantly increased by stroma adherence (35% ± 6% v 15% ± 4%, P ≤ .005) and mafosfamide (100 μg/mL) incubation of marrow cells before stroma adherence (58% ± 9% v 35% ± 6%, P ≤ .005). An additive effect was observed by combining mafosfamide treatment and stroma adherence. Single-colony transfer experiments showed that 50% ± 4% stroma-adherent and 70% ± 4% stroma-adherent mafosfamide-treated progenitors gave rise to secondary colonies. To further characterize the stroma-adherent fraction, experiments were performed in which CD34+ marrow cells were used. The mean (± SEM) output of progenitors generated by 10,000 CD34+, stroma-adherent cells was 888 ± 188 and 570 ± 258 for untreated and maf-osfamide-treated cells, respectively. Individual colonies were analyzed by single-colony karyotyping and fluorescent in situ hybridization using a biotinylated cosmid DNA probe that hybridize to abl oncogene. The CD34+, stroma-adherent fraction contained 38% ± 14% (untreated) and 56% ± 18% (mafosfamide-treated) (P ≤ .025) Ph- progenitors. In conclusion, the present data show the possibility to select Ph- clones that (1) have a maintained capability of stroma adherence, (2) are mafosfamide resistant, (3) are derived from the CD34+ fraction, and (4) have high-replating potential.

A proposed staging system for chronic myeloid leukemia

A staging system was proposed for chronic myeloid leukemia (CML) that groups patients into three stages (I, II, and III), each with two subclasses (A and B). The system uses pathologic parameters, of which the percentage of blasts in the blood and bone marrow is the most important. CML is defined as a myeloproliferative disorder with molecular or cytogenetic evidence of the translocation of the abl oncogene on chromosome 9 to the break-point cluster region gene on chromosome 22. The proposed staging system is similar to format to the standard TNM system used for many solid tumors.

Induction of BCR-ABL fusion genes by in vitro X-irradiation.

The Philadelphia chromosome consists of a reciprocal translocation between the ABL oncogene at chromosome 9q34 and the BCR gene at chromosome 22q1l, resulting in the expression of chimeric BCR‐ABL mRNAs specific to chronic myelogenous leukemia (CML). Presence of the fusion gene can be detected with high specificity and sensitivity by means of reverse transcription and polymerase chain reaction. Using this assay, it was possible to detect BCR‐ABL fusion genes induced among HL60 cells after 100 Gy of X‐irradiation in vitro. In total, five fusion gene transcripts were obtained among 108 cells examined. These fusion genes contained not only CML‐specific BCR‐ABL rearrangements, but also other forms of BCR‐ABL fusions. These latter genes had junctions of BCR exon 4/ABL exon 2 intervened by a segment of DNA of unknown origin, BCR exon 5/ABL exon 2, and BCR exon 4/ABL exon 2. The results appear to be direct evidence for the induction of the BCR‐ABL fusion gene by X‐irradiation. In terms of leukemogenesis, it appears that only those cells bearing certain CML‐related BCR‐ABL fusion genes are positively selected by virtue of a growth advantage in vivo.

Chromosomal approaches to hematopoietic oncogenesis.

Cytogenetic studies have provided an important approach to the identification of genes involved in the development of human leukemias and lymphomas and the "mutational" mechanisms leading to the altered function of these genes. Molecular dissection of chromosome translocations, in both lymphoid and myeloid tumors, has been particularly productive. Involvement of the c-myc gene has been demonstrated in both B cell and T cell tumors through association with an immunoglobulin or T cell receptor locus, respectively, and more than a dozen previously unknown "oncogenes" have been identified in other lymphoid tumor subgroups and are "activated" by a similar mechanism or by formation of a "fusion" gene with a locus on a different chromosome. In myeloid tumors, dissection of the translocation in Philadelphia chromosome positive leukemias has demonstrated involvement of the abl oncogene; other genes, both known and previously unknown, are beginning to be identified in translocations that characterize other classes of myeloid leukemia. These kinds of studies are being extended to search for tumor suppressor genes in association with chromosomal deletions, and some of the new molecular data are already being usefully applied in clinical diagnosis and management. Ultimately, there may also be specific therapies developed from these recent findings, but the recognition of how many different genes are involved has also indicated that no single, simple answer will be forthcoming.

骨髄腫によるＳ型アミラーゼ産生

A patient with IgA lambda type multiple myeloma who appeared to be secreting salivary type amylase ectopically is reported. An amylase producing cell line, KHM-1B was established from the patient. Chromosome analysis of KHM-1B showed many qualitative and quantitative abnormalities including a translocation between 1p 13 or 21, near the amylase gene locus, and 9q 34, the abl oncogene locus. These finding suggest that the amylase gene in KHM-1B is activated by the translocation. A rearranged amylase gene was demonstrated by Southern blot analysis with only one enzyme, Accl. Since we reported the first case of amylase-producing myeloma, eleven other cased have been successively reported in the Japanese literature.

A genetic linkage map of human chromosome 9q

A genetic linkage map of human chromosome 9q, spanning a sex-equal distance of 125 cM, has been developed by genotyping 26 loci in the Venezuelan Reference Pedigree. The loci include 12 anonymous microsatellite markers reported by Kwiatkowski et al. (1992), several classical systems previously assigned to chromosome 9q, and polymorphisms for the genes tenacin (HXB), gelsolin (GSN), adenylate kinase 1 (AK1), arginosuccinate synthetase (ASS), ABL oncogene (ABL1), ABO blood group (ABO), and dopamine beta-hydroxylase (DBH). Only a marginally significant sex difference is found along the entire length of the map and results from one interval, between D9S58 and D9S59, that displays an excess of female recombination. A comparison of the genetic map to the existing physical data suggests that there is increased recombination in the 9q34 region with a recombination event occurring every 125-400 kb. This map should be useful in further characterizing the relationship between physical distance and genetic distance, as well as for genetic linkage studies of diseases that map to chromosome 9q, including multiple self-healing squamous epithelioma (MSSE), Gorlin syndrome (NBCCS), xeroderma pigmentosum (XPA), nail-patella syndrome (NPS1), torsion dystonia (DYT1), and tuberous sclerosis (TSC1).