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1.
Pediatr Rheumatol Online J ; 20(1): 78, 2022 Sep 05.
Article in English | MEDLINE | ID: mdl-36064566

ABSTRACT

BACKGROUND: A20 haploinsufficiency (HA20) is a newly introduced autosomal dominant autoinflammatory disorder, also known as Behcet's-like disease. Some of the most common symptoms of the disease are recurrent oral, genital, and/or gastrointestinal (GI) ulcers, episodic fever, musculoskeletal symptoms, cutaneous lesions, and recurrent infections. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of multi-organ failure due to excessive immune activation. HLH has been reported in a few HA20 patients. Herein, we report two children with the primary presentation of HLH, with a mutation in TNFAIP3, in favor of HA20. CASE PRESENTATIONS: Our first patient was a 4-month-old boy who presented with fever, irritability, pallor, and hepatosplenomegaly. Pancytopenia, elevated ferritin, and decreased fibrinogen levels were found in laboratory evaluation. He was diagnosed with HLH and was treated with methylprednisolone and cyclosporine. Two years later, whole exome sequencing (WES) indicated a mutation in TNFAIP3 at NM_001270507: exon3: c.C386T, p.T129M, consistent with A20 haploinsufficiency. Etanercept, a TNF inhibitor, was prescribed, but the parents were reluctant to initiate the therapy. The patient passed away with the clinical picture of cerebral hemorrhage. The second patient was a 3-month-old boy who presented with a fever and hepatosplenomegaly. Laboratory evaluation found pancytopenia, hyperferritinemia, hypoalbuminemia, hypertriglyceridemia, and hypofibrinogenemia. With the establishment of the HLH diagnosis, he was treated with etoposide, dexamethasone, and cyclosporine, and recovered. WES results revealed a heterozygous de novo variant of TNFAIP3 (c. T824C in exon 6, 6q23.3) that leads to a proline to leucine amino acid change (p. L275P). He was treated with etanercept and has been symptom-free afterward. CONCLUSIONS: This report is a hypothesis for developing of the HLH phenotype in the presence of TNFAIP3 mutation. Our results provide a new perspective on the role of TNFAIP3 mutation in HLH phenotypes, but more extensive studies are required to confirm these preliminary results.


Subject(s)
Cyclosporins , Lymphohistiocytosis, Hemophagocytic , Pancytopenia , Cyclosporins/genetics , Etanercept , Haploinsufficiency/genetics , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/genetics , Male , Mutation , Phenotype , Tumor Necrosis Factor alpha-Induced Protein 3/genetics
2.
Exp Clin Transplant ; 20(Suppl 3): 45-48, 2022 05.
Article in English | MEDLINE | ID: mdl-35570599

ABSTRACT

Membranoproliferative glomerulonephritis and renal microangiopathies may manifest similar clinical presentations and histology. Many genetic mutations that cause these diseases have been reported. Studies on mutations in the gene encoding diacylglycerol kinase epsilon identified a novel pathophysiologic mechanism leading to atypical hemolytic uremic syndrome and/or membranoproliferative glomerulonephritis. Here, we present the different clinical presentations and treatments in 4 family members who carried the same homozygous diacylglycerol kinase epsilon mutation. The first patient (age 5 years, 3 months old at diagnosis) had nephrotic syndrome. The kidney biopsy was membranoproliferative glomerulonephritis; partial remission was achieved with cyclophosphamide, cyclosporine, and mycophenolate mofetil treatment. The second patient (age 5 years, 7 months at diagnosis) presented with overlapping atypical hemolytic uremic syndrome and membranoproliferative glomerulonephritis. Remission could not be achieved with cyclophosphamide, cyclosporine, and mycophenolate mofetil, and hemodialysis treatment was started. At 10 years from first admission, the patient had end-stage kidney disease, and kidney transplant was performed successfully. The third patient was admitted with the diagnosis of nephrotic syndrome at 13 months of age, kidney biopsy showed membranoproliferative glomerulonephritis, and spontaneous remission developed during followup. He presented with hemolytic uremic syndrome 15 months after the first admission, and dialysis was started. Remission was achieved with plasma infusion and eculizumab treatment. The fourth patient (a 7-month-old boy and brother of patient 3) had no clinical or laboratory findings. All patients had genetic analysis, and mutation in exon 2:c.473G>A(p. W158*) was detected. Our related patients with the same mutation showed different clinical and histological findings. However, we did not observe a clear genotype-phenotype correlation in patients with diacylglycerol kinase epsilon nephropathy, suggesting additional factors mediating phenotypic heterogeneity.


Subject(s)
Atypical Hemolytic Uremic Syndrome , Cyclosporins , Glomerulonephritis, Membranoproliferative , Nephrotic Syndrome , Atypical Hemolytic Uremic Syndrome/drug therapy , Cyclophosphamide/therapeutic use , Cyclosporins/genetics , Cyclosporins/therapeutic use , Diacylglycerol Kinase/genetics , Diacylglycerol Kinase/therapeutic use , Family , Glomerulonephritis, Membranoproliferative/genetics , Glomerulonephritis, Membranoproliferative/pathology , Glomerulonephritis, Membranoproliferative/therapy , Homozygote , Humans , Male , Mutation , Mycophenolic Acid/therapeutic use , Nephrotic Syndrome/diagnosis , Nephrotic Syndrome/drug therapy , Nephrotic Syndrome/genetics , Treatment Outcome
4.
J Neuroendocrinol ; 8(5): 395-401, 1996 May.
Article in English | MEDLINE | ID: mdl-8736439

ABSTRACT

A solution-hybridization S1-nuclease protection assay was used to evaluate the expression of messenger RNAs for the activin beta A subunit and type II activin receptor in adult rat brain. Results indicate the presence of beta A subunit mRNA in both hypothalamus and brainstem, with approximately two-fold higher levels in brainstem. Levels of activin type II receptor mRNA were similar in the hypothalamus of young virgin and 15-day lactating females, and in females in which pups were removed after a 5-day lactation period. Male rats castrated prepubertally (30 days p.n.) had approximately 220% higher (P < 0.05) hypothalamic activin type II receptor mRNA levels than postpubertal, 3-month old age-matched sham controls. Two month treatment of castrate rats with estradiol (200 ng/g, i.p. every 2 days) reduced hypothalamic activin type II receptor mRNA expression to control levels; the same dose of testosterone had no effect. The expression of the hypothalamic activin type II receptor gene may be estrogen-regulated in vivo.


Subject(s)
Estradiol/pharmacology , Hypothalamus/chemistry , Receptors, Growth Factor/genetics , Activin Receptors , Amino Acid Isomerases/genetics , Animals , Blotting, Northern , Carrier Proteins/genetics , Cyclosporins/genetics , Female , Gene Expression Regulation/drug effects , Lactation/physiology , Male , Orchiectomy , Peptidylprolyl Isomerase , Protein Serine-Threonine Kinases/drug effects , Protein Serine-Threonine Kinases/genetics , RNA, Messenger/metabolism , Rats , Rats, Inbred Strains , Receptors, Growth Factor/drug effects , Testosterone/pharmacology , Weaning
5.
Gene ; 111(1): 85-92, 1992 Feb 01.
Article in English | MEDLINE | ID: mdl-1547957

ABSTRACT

Cyclophilins (Cyps) constitute a highly conserved family of proteins present in a wide variety of organisms. Historically, Cyps were first identified by their ability to bind the immunosuppressive agent cyclosporin A (CsA) with high affinity; they later were found to have peptidyl-prolyl cis-trans isomerase (PPIase) activity, which catalyzes the folding of oligopeptides at proline-peptide bonds in vitro and may be important for protein folding in vivo. Cells of Saccharomyces cerevisiae contain at least two distinct Cyp-related PPIases encoded by the genes CYP1 and CYP2. A yeast strain (GL81) containing genomic disruptions of three known yeast PPIase-encoding genes [CYP1, CYP2 and RBP1 (for rapamycin-binding protein); Koltin et al., Mol. Cell. Biol. 11 (1991) 1718-1723] was previously constructed and found to be viable. Soluble fractions of these cells possess residual CsA-sensitive PPIase activity (2-5% of that present in wild-type cells as assayed in vitro). We have purified an approx. 18-kDa protein exhibiting PPIase activity from a soluble fraction of GL81 cells and determined that its N-terminal amino acid (aa) sequence exhibits significant homology (but nonidentity) to the Cyp1 and Cyp2 proteins. We designate the gene for this new protein, CYP3. Using a degenerate oligodeoxyribonucleotide (oligo) based on the N-terminal aa sequence, plus an internal oligo homologous to a conserved region within the portion of CYP1 and CYP2 that had been deleted in the genome, a CYP3-specific DNA fragment was generated by the polymerase chain reaction (PCR) using GL81 genomic DNA as a substrate. This PCR fragment was used as a probe to isolate CYP3 genomic and cDNA clones.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Amino Acid Isomerases/genetics , Carrier Proteins/genetics , Cyclosporins/genetics , Isoenzymes/genetics , Multigene Family , Saccharomyces cerevisiae/genetics , Amino Acid Isomerases/isolation & purification , Amino Acid Isomerases/metabolism , Amino Acid Sequence , Base Sequence , Carrier Proteins/isolation & purification , Carrier Proteins/metabolism , Cloning, Molecular , Cyclosporins/isolation & purification , Cyclosporins/metabolism , DNA, Fungal , Genetic Linkage , Isoenzymes/isolation & purification , Isoenzymes/metabolism , Molecular Sequence Data , Peptidylprolyl Isomerase , Polymerase Chain Reaction , Saccharomyces cerevisiae/enzymology , Sequence Alignment
6.
Cytogenet Cell Genet ; 60(3-4): 219-21, 1992.
Article in English | MEDLINE | ID: mdl-1505219

ABSTRACT

The polymerase chain reaction (PCR) technique was used to generate a unique probe complementary to the hydrophobic 5' end of the human cyclophilin B gene. This unique probe was hybridized to DNAs from human x hamster hybrid somatic cell lines retaining different combinations of human chromosomes. The gene was assigned to chromosome 15.


Subject(s)
Amino Acid Isomerases/genetics , Carrier Proteins/genetics , Chromosomes, Human, Pair 15 , Cyclosporins/genetics , Base Sequence , Blotting, Northern , Blotting, Southern , Chromosome Mapping , DNA Probes/genetics , Humans , Hybrid Cells , Molecular Sequence Data , Oligodeoxyribonucleotides/genetics , Peptidylprolyl Isomerase , Polymerase Chain Reaction
7.
Yeast ; 7(9): 971-9, 1991 Dec.
Article in English | MEDLINE | ID: mdl-1803821

ABSTRACT

The nucleotide sequence of a 1558 bp DNA fragment from the right arm of chromosome III of Saccharomyces cerevisiae contains an open reading frame of 954 nucleotides with coding potential for a protein with high similarity to the ubiquitous cyclophilins which are both peptidyl-prolyl cis-trans isomerases and cyclosporin A-binding proteins. It should, therefore, represent the third gene (SCC3) of this kind from S. cerevisiae. SCC3 is present in a single copy in the genome of S. cerevisiae and results in a constitutively expressed 1.2 kb transcript during cell growth. Its putative protein product (Scc3) contains two hydrophobic cores, one at the amino terminal, 20 amino acids long, which could serve as a signal peptide, and the other one at the carboxyl end with a structure similar to a transmembrane helix. These findings suggest that Scc3 could be a secretory or, more likely, a transmembrane protein. The only cyclophilin with similar structure to that of Scc3 is ninaA from Drosophila melanogaster, a transmembrane protein which seems to be implicated in the correct folding and/or intercalation of rhodopsin in the endoplasmic reticulum of the fly photoreceptors (Stamnes, M.A. et al., Cell 65, 219-227, 1991). In addition, the amino and the carboxy regions of Scc3 and ninaA share a significant level of homology, which suggests that they have a similar function, albeit for different target proteins.


Subject(s)
Amino Acid Isomerases/genetics , Carrier Proteins/genetics , Cyclosporins/genetics , DNA, Fungal/chemistry , Saccharomyces cerevisiae/genetics , Amino Acid Isomerases/chemistry , Amino Acid Sequence , Animals , Base Sequence , Blotting, Northern , Blotting, Southern , Carrier Proteins/chemistry , Cloning, Molecular , Cyclosporins/chemistry , DNA, Fungal/analysis , Drosophila melanogaster/genetics , Escherichia coli/enzymology , Escherichia coli/genetics , Genes, Fungal , Molecular Sequence Data , Open Reading Frames , Peptidylprolyl Isomerase , Restriction Mapping , Saccharomyces cerevisiae/chemistry
8.
Biochim Biophys Acta ; 1129(1): 13-22, 1991 Dec 02.
Article in English | MEDLINE | ID: mdl-1756174

ABSTRACT

Fractionation of differentiating murine teratocarcinoma F9 cells and extraction of the nuclear/microsomal pellets with ethidium bromide led to the purification and microsequencing of the protein mCyP-S1, a novel cyclosporin A-sensitive peptidyl-prolyl cis-trans isomerase (PPIase). mCyP-S1 is a new member of the cyclophilin class of proteins. Cloning and sequencing of the mCyP-S1 cDNA revealed extended coding capacity for a putative N-terminal signal sequence, suggesting processing of mCyP-S1 during intracellular translocation across the membrane of the endoplasmic reticulum. mCyP-S1 is abundantly expressed in a variety of mouse organ tissues and its mRNA levels increase during F9 cell differentiation. Specific subcellular localization of PPIases is postulated to contribute to functional specificities of this class of enzymes.


Subject(s)
Amino Acid Isomerases/genetics , Carrier Proteins/genetics , Cyclophilins , Mice/genetics , Amino Acid Sequence , Animals , Base Sequence , Blotting, Southern , Cell Differentiation/genetics , Cloning, Molecular , Cyclosporins/genetics , Gene Expression/genetics , Molecular Sequence Data , Peptidylprolyl Isomerase , Protein Sorting Signals/genetics , Sequence Alignment , Sequence Homology, Nucleic Acid , Tumor Cells, Cultured
9.
Endocrinology ; 128(6): 2702-8, 1991 Jun.
Article in English | MEDLINE | ID: mdl-2036956

ABSTRACT

The rat preoptic area-anterior hypothalamic continuum (POA-AH) contains about 400-800 neurons that express the decapeptide GnRH and the 56-amino-acid GnRH-associated peptide. Originating from the olfactory placode, these neurons migrate and establish their final distribution and connections in the POA-AH several days before birth. The aim of the present study was to examine whether the biosynthesis of the mRNA encoding the precursor (proGnRH) common to GnRH and GnRH-associated peptide undergoes postnatal changes corresponding to the development of sexual maturation. The POA-AH content of proGnRH messenger RNA (mRNA) was followed from postnatal day 1 to day 90 in female and male Sprague-Dawley rats killed by decapitation between 1000-1200 h. Cytoplasmic RNA fractionated from individual POA-AH homogenates was purified using proteinase K digestion. Cytoplasmic proGnRH mRNA was quantitated simultaneously with cyclophilin mRNA (an internal standard control) using solution hybridization-RNase protection assay, with the protected fragments separated through polyacrylamide gel electrophoresis. In the POA-AH, the concentrations of proGnRH mRNA (femtograms mRNA per microgram total RNA) increased significantly with age in both sexes (P less than 0.001). In males, proGnRH mRNA levels increased by day 30 some 2-fold over the values of days 5 and 10, and the levels established on day 30 were maintained through adulthood. In females, the first rise in proGnRH mRNA levels occurred on day 30, followed by an additional increase on day 45 to levels seen in adulthood. Levels of proGnRH mRNA established in adulthood were significantly higher in females than in males (P less than 0.03). The concentrations of cyclophilin mRNA (picograms mRNA per microgram total RNA) remained essentially unchanged in both sexes during the same period of time when proGnRH mRNA levels were increasing. These results provide evidence for postnatal sex-related increases in the levels of proGnRH mRNA in the rat POA-AH, which are likely to reflect differential regulation by gonadal steroids.


Subject(s)
Amino Acid Isomerases/genetics , Animals, Newborn/growth & development , Brain/physiology , Carrier Proteins/genetics , Gene Expression Regulation , Gonadotropin-Releasing Hormone/genetics , Animals , Animals, Newborn/metabolism , Animals, Newborn/physiology , Brain/growth & development , Cyclosporins/genetics , Female , Hypothalamus, Anterior/metabolism , Male , Olfactory Pathways/metabolism , Peptidylprolyl Isomerase , Preoptic Area/metabolism , RNA, Messenger/metabolism , Rats , Rats, Inbred Strains
10.
Biochemistry ; 30(12): 3041-8, 1991 Mar 26.
Article in English | MEDLINE | ID: mdl-2007139

ABSTRACT

Peptidylprolyl-cis-trans-isomerase (PPIase) is thought to be essential for protein folding in the cell. Two forms, a and b, of PPIase and their corresponding genes were isolated from Escherichia coli cells. Despite their insensitivity to cyclosporin A (CsA), both amino acid sequences were homologous and related to that of pig cyclophilin, a protein that has PPIase activity sensitive to CsA (Takahashi et al., 1989). PPIase a is found to be identical with the E. coli ORF 190 gene product that was sequenced by Kawamukai et al. (1989) and overexpressed by Liu and Walsh (1990). It is translocated into E. coli periplasmic space with the signal sequence. PPIase b lacks a hydrophobic amino acid stretch which could serve as a signal sequence or a transmembrane domain, and it is detected mainly in the bacterial cytoplasm. These findings indicate that proteins with the ability to assist folding of various polypeptides are located on both sides of the inner membrane. Thus, we propose that the folding of some exported proteins may be catalyzed by the periplasmic proline isomerase and, in turn, that some proteins which have isomerized may not be translocated efficiently.


Subject(s)
Amino Acid Isomerases/metabolism , Carrier Proteins/metabolism , Escherichia coli/enzymology , Amino Acid Isomerases/genetics , Amino Acid Sequence , Blotting, Southern , Carrier Proteins/genetics , Cloning, Molecular , Cyclosporins/genetics , Cyclosporins/metabolism , Cytoplasm/enzymology , DNA, Bacterial/analysis , DNA, Bacterial/genetics , Electrophoresis, Polyacrylamide Gel , Isoelectric Focusing , Molecular Sequence Data , Peptidylprolyl Isomerase , Protein Conformation , Sequence Homology, Nucleic Acid
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