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PubMed1999

Progression of cardiomyopathy and neuropathy after liver transplantation in a patient with familial amyloidotic polyneuropathy caused by tyrosine-77 transthyretin variant.

Familial amyloidotic polyneuropathy is an inherited form of amyloidosis associated with a mutant form of a protein called transthyretin. The Methionine-30 variant is the most frequent mutation observed. This disorder is caused by deposition of this protein as amyloid in several organs, such as the heart, kidneys, and peripheral nervous system. The disease is always progressive and fatal, and patients die 7 to 10 years after the onset of symptoms. Liver transplantation is at present the only choice for these patients because it provides improvement of symptoms and/or stops progression of the disease in most patients. We report the case of a patient who showed clear progression of cardiomyopathy and neuropathy after liver transplantation.

Amyloid Neuropathies↗
PubMed2003

Clinical and imaging features of autoimmune pancreatitis with focal pancreatic swelling or mass formation: comparison with so-called tumor-forming pancreatitis and pancreatic carcinoma.

OBJECTIVES: Autoimmune pancreatitis (AIP) with a mass formation or swollen pancreas located in one or two segments of the gland (focal type AIP) has been reported. The aims of this study were to elucidate the relationship of the disease entity between this focal variant and so-called tumor-forming pancreatitis (TFP) and to describe the clinical and imaging features discriminating focal AIP from pancreatic carcinoma (Pca). METHODS: The clinical, radiologic, and pathologic profiles of nine patients with focal AIP were reviewed retrospectively and compared with those of 11 patients with alcohol-induced TFP and 80 patients with Pca. RESULTS: The patients with focal AIP were predominantly older (mean age 64.7 +/- 13.6 yr, range 28-78 yr), male, and presenting with obstructive jaundice or focal pancreatic enlargement accompanied by mild abdominal symptoms. In comparison, the patients with alcohol-induced TFP who were mostly middle-aged (mean age 50.1 +/- 7.95 yr, range 39-62 yr), male, and often had attacks of pancreatitis associated with findings of CT scans showing pseudocysts or peripancreatic effusion. Focal AIP usually demonstrated no abnormalities on pancreatograms downstream from the stricture or obstruction and often presented few contrast-filled side branches in the area of main pancreatic duct (MPD) stenosis. These characteristics were similar to the imaging features of Pca. Significant factors differentiating focal AIP from Pca were lower serum levels of CA19-9, homogeneous delayed enhancement evident in dynamic CT scans, and ERCP findings exhibiting a longer stenosed MPD and a thinner MPD upstream from the stricture. CONCLUSIONS: Focal AIP is associated with clinical and radiologic features that are different from those of alcohol-induced TFP. In TFP there are two causative factors, namely, AIP and alcohol-induced chronic pancreatitis. Differential diagnosis of focal AIP from Pca seems to be possible in many cases by evaluating imaging findings such as dynamic CT and ERCP, although focal AIP sometimes shows clinical and radiologic features similar to those of Pca.

Adult↗
PubMed1990

Venous anomalies and abnormalities of the posterior fossa.

The authors report a series of 16 patients with venous anomalies or abnormalities of the posterior fossa studied by angiography, CT and/or MRI. We believe that so-called venous angiomas are extreme anatomic variants that drain normal territories, and we prefer to call them developmental venous anomalies (DVAs). Posterior fossa DVAs, like the supratentorial ones are classified according to their drainage into deep and superficial types. They are exclusively located in the cerebellum or tectum. In 4 cases DVA was an incidental finding; in 3 an associated cerebral venous malformation (CVM) was found and felt to be the cause of the symptoms; and only in one (with trigeminal pain) was a link between both suspected. Cavernous venous malformations (CVMs) were found in frequent association with DVA (27%). Four cases were single and 2 multiple. Five CVMs were located in the brain stem and 3 in the cerebellum. The clinical and radiological files were reviewed and a direct relationship between symptoms and localization was found in all patients with CVM. In 2 cases venous dysplasia was found: 1 Sturge-Weber and 1 first branchial arch syndrome. Both posterior fossa venous abnormalities were incidental findings.

Adolescent↗
PubMed2006

Almost all human genes resulted from ancient duplication.

Results of protein sequence comparison at open criterion show a very large number of relationships that have, up to now, gone unreported. The relationships suggest many ancient events of gene duplication. It is well known that gene duplication has been a major process in the evolution of genomes. A collection of human genes that have known functions have been examined for a history of gene duplications detected by means of amino acid sequence similarity by using BLASTp with an expectation of two or less (open criterion). Because the collection of genes in build 35 includes sets of transcript variants, all genes of known function were collected, and only the longest transcription variant was included, yielding a 13,298-member library called KGMV (for known genes maximum variant). When all lengths of matches are accepted, >97% of human genes show significant matches to each other. Many form matches with a large number of other different proteins, showing that most genes are made up from parts of many others as a result of ancient events of duplication. To support the use of the open criterion, all of the members of the KGMV library were twice replaced with random protein sequences of the same length and average composition, and all were compared with each other with BLASTp at expectation two or less. The set of matches averaged 0.35% of that observed for the KGMV set of proteins.

Amino Acid Sequence↗
PubMed1980

A new unstable PI M variant of alpha 1-antitrypsin in a Finnish isolate.

During family and population studies in a Finnish isolate (Salla), a variant of alpha 1-antitrypsin, tentatively called PI MSAL was found. On isoelectric focusing this variant was slightly cathodal to M3. With the aid of acid starch gel electrophoresis, differentiation from M3 proved reliable, because the variant was unstable in that system. The variant also showed an increased lability at + 56 degrees C and physiological pH and a decreased stability at pH 4.5 and room temperature compared to the other M subtypes. By genealogical studies it was possible to trace a common ancestor, a settler arriving to the parish around 1680, for the three families where the variant was found.

Electrophoresis, Starch Gel↗
PubMed2006

Reservoir cells no longer detectable after a heterologous SHIV challenge with the synthetic HIV-1 Tat Oyi vaccine.

BACKGROUND: Extra-cellular roles of Tat might be the main cause of maintenance of HIV-1 infected CD4 T cells or reservoir cells. We developed a synthetic vaccine based on a Tat variant of 101 residues called Tat Oyi, which was identified in HIV infected patients in Africa who did not progress to AIDS. We compared, using rabbits, different adjuvants authorized for human use to test on ELISA the recognition of Tat variants from the five main HIV-1 subtypes. A formulation was tested on macaques followed by a SHIV challenge with a European strain. RESULTS: Tat Oyi with Montanide or Calcium Phosphate gave rabbit sera able to recognize all Tat variants. Five on seven Tat Oyi vaccinated macaques showed a better control of viremia compared to control macaques and an increase of CD8 T cells was observed only on Tat Oyi vaccinated macaques. Reservoir cells were not detectable at 56 days post-challenge in all Tat Oyi vaccinated macaques but not in the controls. CONCLUSION: The Tat Oyi vaccine should be efficient worldwide. No toxicity was observed on rabbits and macaques. We show in vivo that antibodies against Tat could restore the cellular immunity and make it possible the elimination of reservoir cells.

AIDS Vaccines↗
PubMed1999

Trafficking of the cellular isoform of the prion protein.

Transmissible spongiform encephalopathies form a group of fatal neurodegenerative disorders that have the unique property of being infectious, sporadic or genetic in origin. Although the nature of the responsible agent of these diseases is uncertain, it is clear that a protein called PrPSc has a central role in their pathology. PrPSc is a conformational variant of a normal protein called PrPC. Understanding the transition from PrPC to PrPSc is a major issue in the field. In this article, we will review what is known about the cell biology of PrPC, the understanding of which is crucial considering that trafficking of this molecule governs generation of PrPSc.

Animals↗
PubMed2002

[The prion protein].

Transmissible spongiform encephalopathies form a group of fatal neurodegenerative disorders represented principally by Creutzfeldt-Jakob disease in humans, and by scrapie and bovine spongiform encephalopathy in animals. Also called prion diseases, these disorders have the property of being infectious, sporadic or genetic in origin. Although the nature of the responsible agent of these diseases is uncertain, it is clear that a protein called PrPSc has a central role in their pathology. PrPSc is a conformational variant of a normal protein called PrPC. PrPC is a glycoprotein expressed by most tissues and is attached on the cell membrane by a glycosyl-phosphatidylinositol anchor which would be consistent with roles in cell adhesion, ligand uptake, or transmembrane signaling. NMR studies revealed that the protein has a globular domain and a long amino-terminal tail that contains repeated octapeptide domains which bind metal ions with high affinities. PrPC is localized on the cell membrane in detergent resistant microdomains and may be part of functional complexes with other molecules. This is particularly relevant, knowing the possible role of the molecule in signal transduction, resistance to oxidative stress and neuronal survival. In conclusion, it appears that the understanding of the biology of PrP is essential for the understanding of the physiological function of the protein as well as for its pathological conversion considering that trafficking of this molecule governs generation of PrPSc.

Animals↗
PubMed1991

A family of genes related to a new expression site-associated gene in Trypanosoma equiperdum.

Two genes, belonging to a new expression site-associated gene family of six to eight members in Trypanosoma equiperdum and Trypanosoma brucei, have been cloned from a T. equiperdum variant. One of them, called ESAG-9c, is contained in the 1.78-C expression site and is found just upstream of the 5' barren region. The other one, called ESAG-9u, is unique in the family, is not telomere linked, and apparently is not expression site related. A 2-kb poly(A)+ mRNA is detected with probes for this ESAG-9 family in all T. equiperdum variants examined. By using polymerase chain reaction and restriction fragment length polymorphism techniques, it has been possible to distinguish between ESAG-9c and ESAG-9u and to show that ESAG-9c is transcribed in an expression site-specific manner. However, ESAG-9u (or another gene in the family having identical characteristics) is transcribed in all variants, regardless of the expression site used by these variants. Thus, this ESAG-9 family contains at least one gene that is under expression site control but might have other genes that are not. The function of these ESAG-9 genes is unknown. Transcripts homologous to ESAG-9 were detected in T. brucei bloodstream forms but not in procyclics.

Amino Acid Sequence↗
PubMed1995

Altered (copy-up) forms of initiator protein pi suppress the point mutations inactivating the gamma origin of plasmid R6K.

The R6K gamma origin core contains the P2 promoter, whose -10 and -35 hexamers overlap two of the seven binding sites for the R6K-encoded pi protein. Two mutations, P2-201 and P2-203, which lie within the -35 region of P2, are shown to confer a promoter-down phenotype. We demonstrate here that these mutations prevent replication of a gamma origin core plasmid. To determine whether or not the reduced promoter activity caused by these mutations is responsible for their effect on replication, we generated two new mutations (P2-245-6-7 and P2-246) in the -10 hexamer of the P2 promoter. Although these new mutations inhibit P2 activity as much as the P2-201 and P2-203 mutations, they do not prevent replication of the gamma origin core. Therefore, activity of the P2 promoter does not appear to be required for replication. We also show that the inability of the gamma origin to function in the presence of the P2-201 and P2-203 mutations is reversed by the hyperactive variants of pi protein called copy-up pi. This suppression occurs despite the fact that in vivo dimethyl sulfate methylation protection patterns of the gamma origin iterons are identical in cells producing wild-type pi and those producing copy-up pi variants. We discuss how the P2-201 and P2-203 mutations could inhibit replication of the gamma origin core and what mechanisms might allow the copy-up pi mutants to suppress this deficiency.

Bacterial Proteins↗
PubMedDate not supplied

Clinical features of frontotemporal dementia.

What was once called Pick's disease has three major anatomic variants. With all three, frontotemporal brain is selectively injured whereas posterior cortical regions are spared. These three clinical patterns include a bifrontal, slightly asymmetric subtype with more involvement of the right frontotemporal region called frontotemporal dementia or the frontal variant of FTD (fvFTD), a temporal-predominant subtype called the temporal variant of FTD or semantic dementia (SD), and a left frontal-predominant subtype called progressive nonfluent aphasia (PNFA). The three anatomic groups help to classify distinctive clinical syndromes with unique features. Careful study of these subtypes of frontotemporal dementia, using combinations of new quantitative neuroimaging, behavioral and physiological measures are yielding important information about the functioning of the brain's frontal and temporal regions. As we come to better understand the biologic basis for the three FTD clinical syndromes, new classification schemas may emerge, but our current clinical criteria serve as a strong guide to the diagnosis and separation of FTD from Alzheimer disease and other dementias.

Diagnosis, Differential↗
PubMed1999

Context and sex differences exist in the acoustic structure of phee calls by newly-paired common marmosets (Callithrix jacchus).

Captive common marmosets of all ages robustly produce a "separation" phee call during brief separations from their group. In contrast, a second structural variant, which may function as an intergroup call, is produced in the home cage primarily by the reproductive adults. A previous study found that postpubertal but nonreproductive offspring rarely produce phee calls when in the home cage with the natal group, yet these marmosets call frequently after pairing with an opposite-sex partner. The sudden increase in home cage phee calls may indicate the rapid onset of intergroup calling. Alternatively, marmosets may be producing the separation phee variant as a result of separation from the natal group. The present study investigated whether phee calls produced by recently paired individuals in the home cage were structurally distinguishable from their calls recorded in a separation paradigm. We also tested whether sex differences, known to exist in the calls of mature adults, could be found in calls recorded from younger, nonreproductive animals separated from their natal groups. We analyzed 18 acoustic parameters of phee calls produced in the home cage after pairing and of calls produced during separation both from the natal group and from a new mate. Discriminant function analyses found that home cage calls were clearly discriminable from separation calls (average 91.7% correctly classified), indicating that the rapid increase in home cage phee call production shortly after pairing is not a consequence of separation from the family group. Postpubertal marmosets appear to show a rapid behavioral adjustment to separation from their natal groups. Additionally, sex was clearly discriminable in calls recorded both before and after pairing (average 86.8% correctly classified). Like calls recorded from well-established paired marmosets, phee calls produced by recently paired, postpubertal marmosets are discriminable by context and sex.

Animals↗
PubMed2001

An algorithm for mapping positively selected members of quasispecies-type viruses.

BACKGROUND: Many RNA viruses do not have a single, representative genome but instead form a set of related variants that has been called a quasispecies. The sequence variability of such viruses presents a significant bioinformatics challenge. In order for the sequence information to be understood, the complete mutational spectrum needs to be distilled to a biologically relevant and analyzable representation. RESULTS: Here, we develop a "selection mapping" algorithm--QUASI--that identifies the positively selected variants of viral proteins. The key to the selection mapping algorithm is the identification of particular replacement mutations that are overabundant relative to silent mutations at each codon (e.g., threonine at hemagglutinin position 262). Selection mapping identifies such replacement mutations as positively selected. Conversely, selection mapping recognizes negatively selected variants as mutational "noise" (e.g., serine at hemagglutinin position 262). CONCLUSION: Selection mapping is a fundamental improvement over earlier methods (e.g., dN/dS) that identify positive selection at codons but do not identify which amino acids at these codons confer selective advantage. Using QUASI's selection maps, we characterize the selected mutational landscapes of influenza A H3 hemagglutinin, HIV-1 reverse transcriptase, and HIV-1 gp120.

Algorithms↗
PubMed1990

Thelarche variant: a new syndrome of precocious sexual maturation?

We describe 10 girls (mean age 3.7 years, range 1.9-6.9) with precocious sexual maturation and clinical findings intermediate between those of premature thelarche and central precocious puberty. Studies of spontaneous gonadotropin secretion and ovarian ultrasound morphology also revealed findings intermediate between those of isolated premature thelarche and central precocious puberty. There was no response in 6 of the girls treated with GnRH analogue, whether administered intranasally, sc, or by monthly depot injections. We have called this condition thelarche variant because the gonadotropin independence and cyclical nature of breast development may well be due to a lesion of folliculogenesis.

Body Height↗
PubMed1991

Computational studies of ligand diffusion in globins: I. Leghemoglobin.

The thermally assisted diffusion of a small ligand (carbon monoxide) through a protein matrix (lupine leghemoglobin) is investigated computationally. The diffusion paths are calculated by a variant of the time-dependent Hartree approximation which we call LES (locally enhanced sampling). The variant which was recently introduced by Elber and Karplus is based on the classical TDSCF approximation of Gerber et al. The simulation enables more significant search for diffusion pathways than was possible before. This is done by increasing the number of ligand trajectories using a single trajectory for the protein. We compare qualitatively diffusion rates in leghemoglobin and in myoglobin. The calculation shows that the diffusion in leghemoglobin is much faster than the diffusion in myoglobin, in agreement with experiment. The gate in leghemoglobin is opened by fluctuations at a close contact between the B/C and the G helices. The most relevant fluctuation is the rigid shift of the C helix with respect to the G helix. This path is not observed in a comparable calculation for myoglobin. This finding is rationalized by the lack of the D helix in leghemoglobin and a significantly more flexible CE loop. Supporting experimental evidence for the importance of the CE loop in leghemoglobin can be found in the kinetics studies of Gibson et al.

Amino Acid Sequence↗
PubMed2025

De novo rare EMX2 variants lead to idiopathic hypogonadotropic hypogonadism.

PURPOSE: The genetic etiology of infertility remains unknown. To identify genes for human infertility, we applied a de novo variant analysis in 142 parent-proband trios with idiopathic hypogonadotropic hypogonadism (IHH), an infertility disorder caused by gonadotropin-releasing hormone (GnRH) deficiency. METHODS: Rare de novo copy-number and single-nucleotide variants (CNVs and SNVs) were called from exome sequencing data of the IHH trios. An association study of common EMX2 variants and disease outcomes was performed in the Massachusetts General Brigham Biobank (N = 65,253). GnRH neuronal development and migration was studied in organotypic explants with knocked down of Emx2 and in a mouse model lacking Emx2. RESULTS: We identified that the gene EMX2 harbored both rare de novo CNVs and SNVs. Rare de novo EMX2 variants led to IHH, developmental delay, and hearing loss. Common EMX2 variants were linked to infertility, Parkinson disease, and hearing loss. Knockdown of Emx2 in nasal explants resulted in attenuated GnRH cell migration and GnRH cells were confined to nasal regions of Emx2 knockout (KO) mice, consistent with IHH pathogenesis. CONCLUSION: By utilizing a de novo variant analysis and cellular assays, EMX2 was uncovered as a gene for human infertility.

Humans↗
PubMed2000

The "neurothekeoma": immunohistochemical analysis distinguishes the true nerve sheath myxoma from its mimics.

In contrast with the myxoid variant of neurothekeoma (nerve sheath myxoma), evidence of neurosustentacular (NS) differentiation in the so-called cellular and mixed (intermediate) variants of neurothekeoma remains controversial. In this study, we selected 22 tumors coded as neurothekeoma or nerve sheath myxoma from the Soft Tissue Registry of the AFIP. Each tumor was histologically subtyped as either a myxoid/hypocellular neurothekeoma (MN) (N = 11) or as a "cellular" or "mixed" (intermediate) neurothekeoma variant (C&MV) (n = 11) and analyzed immunohistochemically. The MNs were composed of small, cytologically bland cells arranged in a loose cellular network or in files within highly myxomatous nodules delineated by dense collagen. The tumors showed clear-cut evidence of NS differentiation by exhibiting consistent immunoreactivity for S-100 protein (11 of 11 cases) and low-affinity nerve growth factor receptor, p75(NGFR), (NGFR) (10 of 10), and variable reactivity for glial fibrillary acidic protein (GFAP) (10 of 11) and CD57 (Leu-7) (5 of 9). They also showed pericellular collagen type IV (CIV) expression (9 of 9), scattered intralesional CD34-positive spindled cells (10 of 10), epithelial membrane antigen (EMA)-positive spindled cells located within the adjacent dense collagen (8 of 11), and immunoreactivity for alpha-smooth muscle actin (SMA) (3 of 10) and calponin (4 of 9). In 4 cases, scattered intralesional neuraxons were detected by the Bodian histochemical method or immunohistochemically with anti-neurofilament protein. The tumors had a male-to-female ratio of 6:5, a peak incidence in the 4th decade of life, and an anatomic distribution that included the upper and lower limbs and back. The C&MVs included 9 "mixed" and 2 "cellular" variants. C&MVs differed histologically from MNs by their higher cellularity and presence of larger spindled or epithelioid cells with vesicular nuclei. Immunohistochemically, the tumor cells expressed CIV (9 of 10), calponin (7 of 9), SMA (5 of 10), Leu-7 (1 of 7), S-100 protein (1 of 11), but not NGFR, GFAP, or CD34. EMA-positive spindled cells surrounded tumor fascicles in 1 case. Intralesional neuraxons were not identified. Clinically, these tumors differed from the MNs by exhibiting a male-to-female ratio of 4:7, a peak incidence in the 2nd decade, and an upper body distribution. Our results indicate that the MN shows NS differentiation and is the bona fide nerve sheath tumor, whereas the C&MVs fail to show convincing evidence of NS differentiation and probably warrant a separate classification.

Adolescent↗
PubMed1992

Three novel functional variants of human U5 small nuclear RNA.

We have identified and characterized three new variants of U5 small nuclear RNA (snRNA) from HeLa cells, called U5D, U5E, and U5F. Each variant has a 2,2,7-trimethylguanosine cap and is packaged into an Sm-precipitable small nuclear ribonucleoprotein (snRNP) particle. All retain the evolutionarily invariant 9-base loop at the top of stem 1; however, numerous base changes relative to the abundant forms of U5 snRNA are present in other regions of the RNAs, including a loop that is part of the yeast U5 minimal domain required for viability and has been shown to bind a protein in HeLa extracts. U5E and U5F each constitute 7% of the total U5 population in HeLa cells and are slightly longer than the previously characterized human U5 (A, B, and C) species. U5D, which composes 5% of HeLa cell U5 snRNAs, is present in two forms: a full-length species, U5DL, and a shorter species, U5DS, which is truncated by 15 nucleotides at its 3' end and therefore resembles the short form of U5 (snR7S) in Saccharomyces cerevisiae. We have established conditions that allow specific detection of the individual U5 variants by either Northern blotting (RNA blotting) or primer extension; likewise, U5E and U5F can be specifically and completely degraded in splicing extracts by oligonucleotide-directed RNase H cleavage. All variant U5 snRNAs are assembled into functional particles, as indicated by their immunoprecipitability with anti-(U5) RNP antibodies, their incorporation into the U4/U5/U6 tri-snRNP complex, and their presence in affinity-purified spliceosomes. The higher abundance of these U5 variants in 293 cells compared with that in HeLa cells suggests possible roles in alternative splicing.

Base Sequence↗