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PubMed2000

P18 tumor suppressor gene and progression of oligodendrogliomas to anaplasia.

P18INK4C is a good candidate to be the tumor suppressor gene involved in oligodendrogliomas on 1p32. Loss of heterozygosity on 1p, mutation(s), homozygous deletion(s), and expression of p18 in 30 oligodendroglial tumors were investigated. Loss of heterozygosity on 1p was found in 15 tumors. A p18 mutation was found at an recurrence of an anaplastic oligodendroglioma, but not in the primary, low-grade tumor. No homozygous deletions were found and p18 was expressed in all cases. These results show that p18 alteration is involved in tumor progression in a subset of oligodendrogliomas.

Alleles↗

PubMed2025

MYC Regulates a DNA Repair Gene Expression Program in Small Cell Carcinoma of the Ovary, Hypercalcemic Type.

BACKGROUND/OBJECTIVES: SCCOHT is an aggressive and often fatal cancer that belongs to the ~20% of cancers defined by mutations to subunits of the SWI/SNF chromatin remodeling complex. In SCCOHT, mutations to the SMARCA4 gene, which encodes the SWI/SNF ATPase BRG1, are sufficient to impair SWI/SNF function. This single genetic lesion leads to a cascade of events that promote tumorigenesis, some of which may involve the intersection of SWI/SNF with oncogenic pathways such as those regulated by the MYC oncogene. In SCCOHT tumors and other cancers marked by SWI/SNF subunit mutation, MYC target genes are recurrently activated, pointing to a relationship between SWI/SNF and MYC that has yet to be fully explored. METHODS: In this study, we investigate the contribution of MYC to SCCOHT biology by performing a combination of chromatin binding and transcriptome assays in genetically engineered SCCOHT cell lines, with subsequent validation using patient tumor expression data. RESULTS: We find that MYC binds to thousands of active promoters in the BIN-67 SCCOHT cell line and that the depletion of MYC results in a broad range of gene expression changes with a notable effect on the expression of genes related to DNA repair. We uncover an MYC-regulated DNA repair gene expression program in BIN-67 cells that is antagonized by BRG1 reintroduction. Finally, we identify a DNA repair gene signature that is upregulated in SCCOHT tumors and in tumors defined by loss of the SWI/SNF subunit SNF5. CONCLUSIONS: Collectively, these data implicate MYC as a robust regulator of DNA repair gene expression in SCCOHT and lay a foundation for future studies focused on interrogating the relationship between BRG1 and MYC.

ATR↗

PubMed2003

A2B5 lineages of human astrocytic tumors and their recurrence.

Astrocytomas are very common intracranial glial cell neoplasms with an inherent tendency to progress. However, the heterogeneity of the morphological features and clinical behavior of the tumors makes accurate prognosis based on the histopathological grading system very difficult. Studies demonstrated that astrocytes have two distinctive cell lineages, and tumors arisen from these two astrocytic lineages have been speculated to have different biological and clinical manifestations. The present study aimed to delineate these two astrocytic lineages in human astrocytomas by using different immunohistochemical markers and to correlate the cell lineages of the tumors with their recurrence. Three markers were used, namely the A2B5 antigen, which is present in type 2 astrocytes but absent in type 1 astrocytes, glial fibrillary acidic protein (GFAP), a marker for astrocytes, and galactocerebroside (GC), a marker for oligodendrocytes. It was found that astrocytomas sharing the A2B5+ lineage (A2B5 positive and GFAP positive) have a significantly higher recurrence rate than the tumors of the A2B5- lineage (A2B5 negative and GFAP positive). Immunohistochemical staining and PCR-single-stranded conformational polymorphism analysis showed that p53 overexpression and p53 mutations were closely associated with the recurrent astrocytomas, and p53 abnormalities were more frequently detected in astrocytomas of the A2B5+ lineage. Quantification of proliferation by counting argyrophil nucleolar organizer regions (AgNORs) indicated a higher AgNOR count in the A2B5+ lineage than the A2B5- lineage. Our findings thus suggest that astrocytomas share similar antigenicity with astrocytes, and that the A2B5+ lineage exhibited a higher recurrence rate than the A2B5- lineage. The higher recurrence rate of the A2B5+ tumors may be in part related to the higher frequency of p53 abnormalities found in the tumors and the higher proliferative activity as reflected by the higher AgNOR count of the tumors.

Antigens, Neoplasm↗

PubMed1995

Mutations of the p53 and ras genes in childhood t(1;19)-acute lymphoblastic leukemia.

We have investigated the alterations of p53 and ras genes including H-, K-, and N-ras genes in 22 acute lymphoblastic leukemia (ALL) cases and five cell lines carrying t(1;19) by use of polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis and direct sequencing. The mutations of the p53 gene were found in 2 of 20 t(1;19)-ALL cases at diagnosis (10%), all of 4 cases at relapse (100%), and 4 of the 5 cell lines (80%). Four of the five patients who died had missense mutations at codons 49, 177, 179, and 248. In cases examined sequentially, one had the same point mutation at codon 179 at both diagnosis and relapse, and another had the same p53 gene mutation at codon 240 both in leukemic cells at relapse and in a cell line derived at that time. The other case had no mutation at diagnosis but had the mutation at codon 177 at relapse and cell lines derived from blast cells at diagnosis, suggesting that a small number of leukemic cells with the p53 gene mutation at diagnosis might have escaped PCR-SSCP analysis. In cell lines, SCMC-L9 had three point mutations in the p53 gene at codons 175, 248, and 358, whereas SCMC-L10 had frame shift at codons 209-211. One case had a rare polymorphism at codon 11. We found only one mutation of the N-ras gene that was a 2-bp substitution of GGT(Gly) to GTC(Val) at codon 13 among 22 t(1;19)-ALL cases and five cell lines. This case showed no mutation of the p53 gene and has had a good course. These results suggest that in t(1;19)-ALL, mutations of the p53 and ras genes are infrequent at diagnosis and that p53 gene alterations may be associated with relapse phase or progression of t(1;19)-ALL.

Adolescent↗

PubMed2006

Genetic basis of nephrotic syndrome--review.

Nephrotic syndrome (NS) is one of the most frequent syndromes characterized namely by heavy proteinuria. Majority of NS occurs as a sporadic form, the incidence of familial cases is from 3 to 5%. Seven genes have been recognized till present, which mutations are responsible for severe forms of NS: NPHS1, NPHS2, ACTN4, CD2AP and WT1, TRPC6, LAMB2. Proteins encoded by these genes (nephrin, podocin, alpha-actinin-4, an adapter protein anchoring CD2 and others) influence the function of the podocytes. In cases of mutation in NPHS1 gene, causing congenital nephrotic syndrome of the Finnish type (CNF), resistance to steroid therapy occurs regularly and recurrence of proteinuria after renal transplantation is about 20-25%. Mutations in NPHS2 gene lead to autosomal recessive steroid resistant nephrotic syndrome (histologically focal segmental glomerulosclerosis). It was concluded that patients with steroid resistant nephrotic syndrome (SRNS) with homozygous or compound heterozygous mutations in NPHS2 have reduced risk for recurrence of focal segmental glomerulosclerosis (FSGS) in renal transplant (only 8% in comparison with 35% in patients without mutation in NPHS2). A functional polymorphism of NPHS2 gene--R229Q was associated with a late-onset nephrotic syndrome and also with an increased risk of microalbuminuria in the general population. The R229Q variant encodes a protein with lower affinity for binding nephrin. This polymorphism appears to enhance susceptibility to FSGS in association with a second mutant NPHS2 allele. There are also 3 genetic loci connected with autosomal dominant forms of FSGS: ACTN4, TRPC6 and CD2AP (found only in the mice models). These forms of FSGS differ from the recessive form by later-onset and more slowly progressive course of the disease; these mutations seem to be responsible for only a fraction of the autosomal dominant pattern of FSGS.

Glomerulosclerosis, Focal Segmental↗

PubMed2025

The effect of TERT promoter mutation on predicting meningioma outcomes: a multi-institutional cohort analysis.

BACKGROUND: Molecular aberrations have been incorporated into tumour classification guidelines of meningioma. TERT-promoter (TERTp) mutation is associated with worse prognosis and is designated a WHO grade 3 biomarker. However, it remains unclear whether TERTp mutation is context-dependent, with other co-occurring genetic alterations potentially driving its association with prognosis. We sought to characterise the role of TERTp mutation in meningioma and guide TERTp sequencing. METHODS: We identified 1492 patients of all ages who had previously received surgery for meningioma across 14 medical centres in the USA, Canada, and Germany. Patients were eligible if they had post-surgical clinical or radiographical assessment of the resection site, and TERTp status evaluated by Nov 1, 2024. Multi-modal profiling was used to assess TERTp mutation, focal gene alterations-including CDKN2A/B loss-and copy number alterations. An adjusted WHO grade was calculated for TERTp-mutant meningiomas, incorporating all WHO criteria except TERTp status. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to quantify the effect of TERTp mutation on the endpoints of overall survival and recurrence-free survival across adjusted WHO grade and co-occurring molecular alterations. FINDINGS: 64 (4·3%) of 1492 meningiomas were TERTp-mutant and 1428 (95·7%) were TERTp-wildtype. Of the TERTp-mutant meningiomas, 33 (51·6%) were from female patients and 31 (48·4%) were from male patients, and the overall median age was 67 years (IQR 60-75). Of the wildtype meningiomas, 965 (67·6%) were from female patients and 463 (32·4%) were from male patients, and the overall median age of the patients was 59 years (IQR 48-70). Data on race was inconsistently reported and thus excluded. The TERTp-mutant patients had a 5-year overall survival (49·4% [95% CI 33·7-72·4]) and 5-year recurrence-free survival (27·6% [95% CI 16·8-45·5]) resembling that of patients with WHO grade 3 TERTp-wildtype tumours (5-year overall survival 32·3% [95% CI 17·2-60·5], p=0·28, 5-year recurrence-free survival 14·3% [5·8-35·2], p=0·28). However, the TERTp-mutant group had heterogenous histological grading and was enriched for aggressive molecular features, with 1p loss present in 44 (77·2%) of 57 profiled tumours and CDKN2A/B loss in 24 (41·4%) of the 58 profiled tumours. Adjusting tumour grade revealed a subset of TERTp-mutant meningiomas that were more molecularly and clinically benign. Among TERTp-mutant tumours, CDKN2A/B loss played a defining role in stratifying tumour behaviour. Multivariable analysis confirmed this, with CDKN2A/B loss being significantly associated with shorter overall survival (HR 3·04 [95% CI 1·67-5·52], p=0·00026) and faster time to recurrence (HR 5·22 [95% CI 3·10-8·79], p<0·0001), while TERTp-mutation did not independently affect overall survival (HR 1·00 [95% CI 0·53-1·87], p=0·99) or recurrence-free survival (1·17 [95% CI 0·75-1·83], p=0·49). Sequencing for TERTp-mutation demonstrated clinical impact only among histologically WHO grade 2 meningiomas. INTERPRETATION: The indolent behaviour of certain TERTp-mutant meningiomas suggests that TERTp mutation is not sufficient to assign the most aggressive meningioma grade. Instead, TERT sequencing might offer prognostic utility in identifying high-risk cases among WHO grade 2 meningiomas. FUNDING: National Institutes of Health, National Institute of Neurological Disorders and Stroke, Friedberg Charitable Foundation, Courtney Meningioma Research Fund, Fleming Meningioma Research Fund, and the Gray Family Foundation.

Humans↗

PubMed2004

Novel SBDS mutations caused by gene conversion in Japanese patients with Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS; OMIM 260400) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction and metaphyseal chondrodysplasia. SDS is caused by mutations in SBDS, an uncharacterized gene. A previous study in SDS patients largely of European ancestry found that most SBDS mutations occurred within a approximately 240-bp region of exon 2 and resulted from gene conversion due to recombination with a pseudogene, SBDSP. It is unknown, however, whether these findings are applicable to other ethnic groups. To address this question, we examined SBDS mutations in six Japanese families with SDS by direct sequencing. We identified compound heterozygous mutations in four families: two were recurrent (96-97insA, 258+2T>C), and three were novel [292-295delAAAG, (183-184TA>CT +201A>G), (141C>T+183-184TA>CT+201A>G)] mutations. Most of these mutations also appear to result from gene conversion, but the conversion events occurred at various sites between intron 1 and exon 3. Thus, gene conversion mutations in SBDS are common to different ethnic groups, but they are not confined to a limited region of the gene.

Alleles↗

PubMed2006

PYPAF1 nonsense mutation in a patient with an unusual autoinflammatory syndrome: role of PYPAF1 in inflammation.

OBJECTIVE: To gain insight into the pathophysiology of an unusual autoinflammatory syndrome, in a patient of Armenian origin, that mimicked familial Mediterranean fever (FMF) but with episodes triggered by generalized exposure to cold, and to further elucidate the controversial function of the protein encoded by PYPAF1, whose mutations (exclusively missense to date) have been identified in 3 hereditary recurrent fever syndromes. METHODS: The patient's DNA was screened for mutations in both MEFV, the gene responsible for FMF, and PYPAF1. The ability of different recombinant PYPAF1 isoforms, expressed in HEK 293 cells, to regulate NF-kappaB signaling was subsequently assessed. RESULTS: No disease-causing mutation was found in MEFV. However, a nonsense mutation (p.Arg554X) was identified in PYPAF1; this defect resulted in a truncated protein lacking all leucine-rich repeats. Study of the wild-type and mutant PYPAF1 recombinant proteins revealed that PYPAF1 inhibited NF-kappaB proinflammatory pathways, and that the identified nonsense mutation impaired this property. CONCLUSION: These molecular and clinical findings, together with the clinical manifestations in the patient, which call into question the current nosology of the hereditary recurrent fever syndromes, are consistent with the hypothesis that PYPAF1 acts as an inhibitor of NF-kappaB signaling. They also provide a clear elucidation of the functional consequences of this nonsense PYPAF1 mutation not previously described in the literature, which result in a partial loss of function and may thereby explain the pathophysiology of the autoinflammatory syndrome observed in this patient.

Adolescent↗

PubMed2004

Offspring gender ratio and the rate of recurrent spontaneous miscarriages in jewish women at high risk for breast/ovarian cancer.

BRCA1/BRCA2 germline mutations are associated with an increased breast/ovarian cancer risk. Offspring gender ratios may be skewed against male births in BRCA1 mutation carriers. In addition, the lack of viable homozygous BRCA1/BRCA2-mutation carriers implies that recurrent miscarriages may be associated with homozygous fetuses. Jewish Israeli high-risk women who were tested for being carriers of the predominant BRCA1/BRCA2 mutations in Jewish high-risk families were analyzed for the sex of offspring and the rate of spontaneous miscarriages. Overall, 817 women participated: 393 BRCA1/BRCA2-mutation carriers (229 with breast/ovarian cancer) and 424 high-risk noncarriers (208 with breast/ovarian cancer). No differences between the male-to-female offspring ratios of all study groups were noted. Among mutation carriers, the offspring male-to-female ratio was 0.97 (444 : 460), and among mutation carriers with cancer it was 0.92 (262 : 284). Similarly, no offspring gender skewing was noted among high-risk noncarriers, regardless of health status. The rates of three or more spontaneous miscarriages among participants with at least one live birth were 4.37% (15/343) among mutation carriers and 3% (12/401) among high-risk women (P = not significant). In conclusion, the offspring gender ratio is similar in high-risk Jewish families and in the general population. The issue of the rate of recurrent miscarriages in high-risk Jewish women is unresolved.

Abortion, Habitual↗

PubMed2003

Evolution of hepatitis B virus sequence from a liver transplant recipient with rapid breakthrough despite hepatitis B immune globulin prophylaxis and lamivudine therapy.

Recurrent hepatitis B virus (HBV) infection after liver transplantation can be prevented by prophylactic hepatitis B immune globulin (HBIG) and lamivudine therapy. However, reinfection may still occur due to the emergence of immune escape mutants and mutants of the YMDD motif. The full spectrum of mutations within the HBV genome during recurrent HBV infection remains to be documented. In this study, serial HBV isolates were characterized from a patient with lamivudine resistance prior to liver transplantation who developed recurrent HBV infection within 2 months of transplantation despite a high dose of HBIG and lamivudine therapy. Sequence analysis of full-length viral genome before transplantation revealed many point mutations as compared with a wild-type genotype C sequence, including the T1753G/A1762T/G1764A triple mutation in the basal core promoter and the G1896A nonsense mutation in the precore region. After transplantation and therapy, several point mutations in the HBV genome emerged or became dominant. These mutations caused L426I/L526M/M550I triple mutation (equivalent to L428I/L528M/M552I in previous reports) in the polymerase, and D144E mutation in the "a" determinant of HBsAg. Transfection experiments revealed that the D144E mutation reduced HBsAg affinity to anti-HBs, confirming its active role for immune escape. Our study suggests that mutations in the HBsAg (D144E) and the polymerase (L426I/L526M/M550I) of HBV genome may be responsible for viral breakthrough despite HBIG prophylaxis and lamivudine therapy.

Base Sequence↗

PubMed2007

Febrile seizures are associated with mutation of seizure-related (SEZ) 6, a brain-specific gene.

Genetic factors contribute significantly to the etiology of febrile seizures (FS), the most common type of seizures in childhood. However, in most patients with FS, the causative gene is unknown. The purpose of this study was to explore the relationship between human brain-specific gene SEZ-6 and FS. Through amplification of genomic DNA by PCR and sequencing of the resulting products, we screened 75 subjects for mutations in the coding region (17 exons) of the SEZ-6 gene. Fifteen subjects were healthy individuals and 60 subjects had FS. Patients with FS could be divided into sub-groups based on seizure type (42 simple and 18 complex) and family history (41 had a positive family history). All patients have been followed to date to evaluate seizure recurrence and the development of epilepsy. No mutations were found in healthy controls, but 21 of the patients with FS had mutations in SEZ-6, and the most common type of mutation was a heterozygous, cytosine insertion (frame shift mutation) at position 1435 of the cDNA. The mutation incidence was significantly higher in patients with complex FS (vs. simple FS) and in patients with a positive family history. Sixteen of 42 patients with simple FS experienced seizure recurrence during the 1-5-year follow-up period. Fifteen of 18 patients with complex FS also experienced a recurrence during this period. Among these patients with recurrences, five patients with simple FS and six patients with complex FS have developed epilepsy. The mutation incidence among these epileptic patients is 72.7%. The human SEZ-6 gene is related to the occurrence and development of FS and may be a novel candidate gene for epilepsy. Screening for mutations in SEZ-6 may be valuable in predicting FS recurrence or the development of epilepsy.

Child, Preschool↗

PubMed2000

Preimplantation genetic diagnosis.

Preimplantation genetic diagnosis (PGD) includes a variety of techniques that have been developed to detect the transmission to the offspring of genetic diseases or of chromosome abnormalities by couples at risk before a pregnancy is established, to avoid these couples the risk of recurrent abortions and/or of repeated terminations of pregnancy. Candidate couples are carriers of gene mutations or of structural chromosome rearrangements, or with recurrent spontaneous abortions of unknown origin. Diagnostic procedures include different modalities of gene amplification using the polymerase chain reaction (PCR) or of fluorescent in situ hybridization (FISH). Embryo biopsies are carried out at the 6-8 cell stage. Healthy embryos are transferred on day 4 or at the blastocyst stage. By now, several hundred healthy children have been born using PGD, and only one diagnostic error has been reported.

Abortion, Habitual↗

PubMed1994

p53 gene mutations in breast cancers in midwestern US women: null as well as missense-type mutations are associated with poor prognosis.

We determined the pattern of mutations in exons 2-11 and adjacent intronic regions in breast cancers from Midwestern US white women. Twenty-one mutations were detected in 53 tumors (39.6%). Comparisons of the pattern of mutations within exons 5-9 showed that the frequency of missense mutations (44%) was lower in breast cancers of US Midwestern women than in most tumor types including breast cancers in other populations. Compared to breast cancers reported in a Scottish population, US women had a high frequency of G:C-->T:A transversions (P = 0.046). These findings suggest that environmental or endogenous factors contribute to p53 mutagenesis in mammary tissue to different extents among different populations. With a median follow-up of 19 months, the presence of a mutation was associated with shorter time to disease recurrence (P = 0.05) and shorter survival (P = 0.003). Putative dominant negative missense-type mutations (missense and in-frame microdeletions; P = 0.001) and null mutations (hemizygous nonsense and frameshift mutations; P = 0.007) were equally ominous. Thus, tumors with missense p53 mutations resulting in over-expression of a dysfunctional but otherwise intact protein have a clinical outcome similar to tumors with null mutations resulting in a truncated or garbled protein.

Adult↗

PubMed1998

Factor V Leiden mutation is a risk factor for cerebral venous thrombosis: a case-control study of 55 patients.

BACKGROUND AND PURPOSE: Different coagulation disorders have been associated with cerebral venous thrombosis (CVT). Until now, fewer than 50 patients have been reported with CVT and the factor V Leiden (FVL) mutation. Although the prevalence of FVL-positive patients with CVT ranged from 10% to 25%, it was as low as 0.5% to 3% in the control groups. Most other studies had not systematically searched for concomitant risk factors or previous thromboembolic events. To better define the relevance of the FVL mutation in conjunction with additional risk factors in CVT, we conducted the present case-control study. METHODS: Fifty-five patients with CVT were compared with 272 healthy controls. A standardized interview regarding established risk factors for venous thrombosis and the patients' and their families' histories for thromboembolic events was performed. The presence of the FVL mutation was determined by polymerase chain reaction on DNA obtained from peripheral blood leukocytes. RESULTS: Of 55 patients, 8 (14.5%) were heterozygous for the FVL mutation compared with 17 of 272 controls (6.25%). The relative risk for the presence of FVL was 2.55 (95% confidence interval, 1.04 to 6.26; P=0.04). Additional risk factors for CVT were frequently found in both the presence and absence of FVL. Recurrence of venous thromboembolic events was more frequent in patients with the FVL mutation (5 of 8 patients, 62.5%) than in those without this anomaly (8 of 47 patients, 17%; P<0.005). CONCLUSIONS: Our study confirms the FVL mutation as the most relevant hereditary risk factor for CVT. Coexisting risk factors are usually involved in the initiation of CVT. Patients with the FVL mutation are at an increased risk for recurrent venous thrombosis.

Adolescent↗

PubMedDate not supplied

Liver graft infection by HBV S-gene mutants in transplant patients receiving long-term HBIg prophylaxis.

BACKGROUND/AIMS: HBV reinfection of transplant livers occurs frequently even in the presence of high doses of anti-HBs immunoglobulins. We analyzed, retrospectively, whether and which type of S-gene variants were selected by long-term polyclonal anti-HBs (HBIg) treatment leading to reinfection of patients transplanted because of chronic HBs-positive end-stage liver disease. METHODOLOGY: The preS2/S gene of the viral genomes obtained from sera before transplantation and during HBV reinfection was amplified by PCR and directly sequenced. RESULTS: According to transaminase and HBV DNA hybridization analysis, 3/18 (17%) liver transplant patients had HBV and hepatitis recurrence during anti-HBs therapy. A HBV S-gene mutant containing a G to A nucleotide mutation at position 587, converting Glycine to Arginine (G145A), was identified in all three patients as the dominant population at reinfection but not pre-transplantation. Contrary to the S-gene, no consistent nucleotide changes were found in the pre-S2 region of HBV genomes when comparing the reinfection and pre-transplantation samples. CONCLUSIONS: These data demonstrate that long-term polyclonal anti-HBs immunoprophylaxis selected the most commonly described G145R S-gene escape HBV variant which became the dominant virus population and was responsible for graft infection. Therefore, immunoglobulins with high affinity for the G145R HBs variant should be included in HBIg to prevent recurrent HBV infection in transplant patients.

Adult↗

PubMed2005

Long-term course of lipoprotein lipase (LPL) deficiency due to homozygous LPL(Arita) in a patient with recurrent pancreatitis, retained glucose tolerance, and atherosclerosis.

CONTEXT: Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive disorder caused by LPL gene mutation and is characterized by severe hyperchylomicronemia. Patients with LPL deficiency suffer from the frequent recurrence of acute pancreatitis, but the underlying mechanisms are not fully understood. CASE REPORT: A 22-yr-old male Japanese patient with severe hyperchylomicronemia was admitted to our hospital in 1973. He had no consanguinity and no family history of hyperlipidemia. He was genetically diagnosed as LPL deficiency (homozygous for LPL(Arita)) with no LPL mass or activity in postheparin plasma. He has experienced recurrent acute pancreatitis 22 times during our 31-yr clinical follow-up, but no pancreatic pseudocyst, irregularity of the pancreatic duct, or abnormal pancreatic calcification was observed in computed tomography. Moreover, his pancreatic endocrine function, as assessed by the oral glucose tolerance test, has preserved more than 30 yr. Although he was a current smoker, no clinically significant atherosclerotic lesion had been observed. CONCLUSIONS: From the long-term observation of this patient, we propose that LPL deficiency is not invariably associated with high mortality and that even with repeated episodes of acute pancreatitis, pancreatic function may be slow to decline.

Acute Disease↗

PubMed2000

A murine model of inflammatory bone disease.

We have recently reported the identification of a new recessive mutation on murine chromosome 18 that results in tail kinks and deformity in the lower extremities of mice. Preliminary examination of the bones of these mice showed that there are abnormalities present that resembled chronic recurrent multifocal osteomyelitis. Accordingly, this new mutation was named "CMO." In this report, we describe the histology of bones in CMO mice, as well as the capacity of the bone marrow cells from these animals to form osteoclasts (OCLs). In addition, we tested conditioned media from non-adherent marrow cells and total marrow cells from CMO mice for their capacity to induce OCL formation in normal murine marrow cultures. These studies demonstrated that the bone disease in these animals is inflammatory in nature, and a soluble factor(s) that is not IL-1alpha, IL-6 or TNF-alpha is released by marrow cells from CMO animals and enhances OCL formation in normal murine marrow cultures.

Animals↗

PubMed1999

Listeria monocytogenes and recurrent mycobacterial infections in a child with complete interferon-gamma-receptor (IFNgammaR1) deficiency: mutational analysis and evaluation of therapeutic options.

We describe the history of a girl with interferon-gamma-receptor (IFNgammaR1) deficiency and studies performed to identify the molecular and clinical characteristics of this recently discovered disorder. This is the first report of a child from Northern Europe with IFNgammaR1 deficiency. The patient, now 7 years old, first presented with swelling and reddening at the Bacille Calmette-Guerin (BCG) vaccination site, swelling of lymph nodes, hepatomegaly, and an unusually severe varicella rash at the age of 4 months. At that time, she was diagnosed with BCG histiocytosis without typical granuloma formation and was treated with antituberculous agents. During the clinical course of her illness, several different types of atypical mycobacteria and (for the first time in an IFNgammaR1-deficient patient) Listeria monocytogenes were detected. Flow cytometric analysis showed that the patient's monocytes could not bind a monoclonal antibody specific for the IFNgamma-receptor. Our analysis of mRNA derived from the alpha-chain (IFNgammaR1) gene of this receptor revealed deletions of 173 bp and 4 bp in cDNA sequences originating from individual alleles. The 173 bp deletion was located between nucleotide positions 200 and 372, exactly matching those of exon 3, and the 4 bp deletion was located between nucleotide positions 561 and 564 of the coding region of the cDNA. Analysis of genomic DNA revealed the presence of a G to T transition at the 5'end of the splice consensus sequence of intron 3, which explains the absence of exon 3. The other allele carried the 4-base-pair deletion (ACTC) at nucleotide positions 15-18 of exon 5. Twelve months after an allo\geneic bone marrow transplantation, the patient had clinically improved.

Alleles↗