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PubMed1995

Primary structure of ovine alpha s1-caseins: localization of phosphorylation sites and characterization of genetic variants A, C and D.

The primary structures of ovine alpha s1-casein variants A, C and D (formerly called Welsh variant) were determined. Separation of variants from whole casein was achieved using a fast and reliable reversed-phase HPLC method. Extended structural characterization of the purified proteins using electrospray mass spectrometry, automated Edman degradation and peptide mapping by means of HPLC-fast atom bombardment-mass spectrometry demonstrated that the mature protein was a mixture of two molecular species that differed in the deletion of residues 141-148 and were therefore 199 and 191 residues long respectively. The 199 residue peptide chain, which accounted for approximately 80% of the entire translated alpha s1-casein, was as long as its caprine and bovine counterparts, and had a 98 and 89% degree of identity with those two proteins respectively. Nine serine residues (positions 12, 44, 46, 64 to 68 and 75) were fully phosphorylated in alpha s1-casein A, whereas Ser115 and Ser41 were phosphorylated by approximately 50 and approximately 20% respectively. The differences between the three genetic variants A, C and D were simple silent substitutions, which however involved the degree to which the protein was phosphorylated. Variant C differed from variant A in the substitution Ser13-->Pro13 which determined the loss of the phosphate group on site 12 of the protein chain, SerP12-->Ser12. A further substitution, SerP68-->Asn68 caused the disappearance of both phosphate groups in the phosphorylated residues Ser64 and Ser66 in variant D; in this last casein variant there was no evidence of phosphorylation at Ser41.

Amino Acid Sequence↗
PubMed1992

"Solid" variant of aneurysmal bone cyst.

A case of the so-called "solid" variant of aneurysmal bone cyst is reported. A 12-year-old girl with a few weeks' history of backache presented with a tender palpable mass located thoraco-spinal in the back at Th 3. Radiologically, the lesion was consistent with conventional aneurysmal bone cyst. Morphologically, it showed fibroblastic, fibrohistiocytic, fibromyxoid, osteoclastic and osteoblastic components as well as small aneurysmal sinusoids. Based on four other well documented cases, the clinico-pathological features and the differential diagnostical problems are discussed.

Bone Cysts↗
PubMed1980

Malignant lymphoma with a high content of epithelioid histiocytes: report of T-cell variant of so-called Lennert lymphoma and review of the literature.

The present report describes the first case of well-differentiated nodular lymphocytic lymphoma evolving into Lennert lymphoma of T-cell origin. A 58-year-old white female developed malignant lymphoma, well-differentiated, lymphocytic type, nodular, with focal bone marrow involvement (stage IV) in May 1975. She received 16 cycles of cyclophosphamide and prednisone combination chemotherapy which was completed in October 1976. A complete remission was achieved. In December 1976, she relapsed and was treated with cyclophosphamide, vincristine, bleomycin, and prednisone until May 1977. Lymphadenopathy decreased until August 1978, but then increased again. Biopsy of an axillary lymph node was interpreted as Lennert lymphoma. She received methotrexate, cyclophosphamide, vincristine, adriamycin, and prednisone beginning in September 1978. When last seen in November 1979, she was in partial remission. Lymphoid cells obtained from lymph node which was involved with Lennert lymphoma consisted of 93% standard E-rosettes and 83% gravity E-rosettes. Cytoplasmic immunoglobulin on frozen sections was negative, but acid phosphatase (ACP) and alpha-naphthyl acetate esterase reactions were strongly positive. These findings support a T-cell proliferation in Lennert lymphoma. A review of the literature reveals only four cases of Lennert lymphoma of T-cell origin.

Drug Therapy, Combination↗
PubMed2026

Long-read Sequences Mapped to a Complete Reference Genome Uncover Uncaptured Structural Variants across the Beta-globin Cluster in Africans with Sickle Cell Disease.

African genomes are marked by extensive complexity in the number and distribution of variants, yet remain under-represented in genetic databases and the human reference genome. This gap in representation limits the broad application of genomic medicine. Sickle cell disease (SCD) - one of the most common monogenic diseases - has its highest prevalence in Africa, and variation in disease severity has consistently been linked to the beta-globin locus, including levels of fetal hemoglobin (HbF). Modulation of HbF is central to current SCD gene therapies; however, the inherent complexity and variation at the locus in African genomes presents a challenge to translating these advances to Africa. Here, we align long-read single molecule sequences (LRS) targeted to the beta-globin region to the hg38 and T2T-CHM13v2 genome references in 40 individuals with SCD, predominantly recruited from three African countries. We demonstrate that the expanded T2T-CHM13v2 reference sequence at this locus reduces Structural Variant (SV) calls by 70% and uncovers uncaptured single nucleotide variants (SNVs). Across the cluster we report 343 SVs and 196 SNVs that have not been previously reported, including in LRS data from the All of Us project. By including African populations from ethnolinguistic groups that have not been previously surveyed we improve variant resolution and bolster evidence for observed variation. Finally, we identify a common ∼4kb insertion locus overlapping the HBB promoter among individuals with high HbF. These results demonstrate the utility of combining a comprehensive reference genome with LRS in African populations to uncover genomic variation at disease-associated loci.

SNV↗
PubMed1985

A variant of cerebral glioma called pleomorphic xanthoastrocytoma: case report.

A newly recognized type of cerebral astrocytoma has been described in the last 5 years among patients under the age of 30. The designation of pleomorphic xanthoastrocytoma has been suggested for this neoplasm on the basis of its unique histological features. These include abundant lipid droplets in the astrocytic cytoplasm. We report an additional case of this cerebral hemisphere astrocytoma, which (in common with 17 others reported before) occurred in a young patient. His postoperative course has been benign and he remains ambulatory and almost symptom-free 9 years after the initial tumor excision. The diagnosis of pleomorphic xanthoastrocytoma should be entertained in patients in whom a superficially placed intracerebral tumor (i.e., one that seems to be in contact with the meninges) develops during the juvenile years.

Adolescent↗
PubMed1986

Angiomatous variant of so-called mesothelioma of the atrioventricular node.

A case is presented of an elderly woman found to have an angiomatous tumor involving the atrioventricular (AV) node. The entire AV node was not involved, which explains her lack of symptomatology during her life. The divergent histologic patterns observed in these tumors suggest that the term AV node tumor is preferable to the term mesothelioma.

Aged↗
PubMed1991

Purification and structural study of two albumin variants in an Irish population.

Two types of variant albumins were detected during routine electrophoresis on cellulose acetate on 34,000 sera from patients in a relatively stable Irish population. The fast type (IRE1) (relative mobility 1.05) had a heterozygote frequency of 1/3,780, and the slow type (IRE2) (relative mobility of 0.94) had a heterozygote frequency of 1/8,500. A method for purification of the two types of variants is described. Structural study of the fast variant established a single amino acid substitution 313 lysine----asparagine (313 Lys----Asn); this variant has been reported in several European populations and also in New Guinea indigenes. However, the slow variant has a new substitution, 479 glutamic acid----lysine (479 Glu----Lys). Because it appears to be uniquely Irish, the slow variant (formerly called IRE2) has been renamed albumin Dublin. Three other albumin variants most often reported in European populations (cumulative frequency only about 1/3,500) were not detected in this study. Because of the significance of albumin genetic variants for the study of protein evolution and as an aid in identification of drug-binding sites, clinical chemists are asked to be on the alert for cases of bisalbuminemia.

Adult↗
PubMed1985

Excision repair of UV- or benzo[a]pyrene diol epoxide-induced lesions in xeroderma pigmentosum variant cells is 'error free'.

It is known that cells from one class of xeroderma pigmentosum (XP) patients, called XP variants, carry out excision repair of UV-induced DNA damage at a normal rate and are only slightly more sensitive than normal cells to the cytotoxic effect of UV radiation, but are much more sensitive to the mutagenic effect of UV. To see if this hypermutability were the result of an 'error-prone', excision repair process, we irradiated fibroblasts derived from an XP variant patient, XP4BE, under conditions that allowed the cells various lengths of time for excision repair before the onset of DNA synthesis (S phase) and assayed the frequency of 6-thioguanine (TG)-resistant mutants. Cells synchronized by release from confluence (G0 state) and irradiated just prior to S phase showed a dose-dependent increase in mutants at very high frequencies; cells irradiated in early G1, approximately 12 h before the onset of S phase, showed frequencies 4 times lower. Cells irradiated in the G0 state and allowed 24 h or 48 h for excision repair before the onset of S phase showed still lower frequencies. A comparison of the relative rates of decrease in mutant frequency with time for excision repair before the onset of S phase in XP variant cells and normal human fibroblasts after a dose of 4 or 6 J/m2 showed that these were equal. However, for every time point, the frequency of mutants induced per dose of UV was significantly higher in the XP variant population than in the normal, suggesting that the XP variant cells have an abnormally error-prone process of replicating DNA on a template containing unexcised lesions or normal cells are by-passing many of such lesions using an error-free process. A similar comparative study in synchronized populations of XP4BE cells and normal cells, using the anti 7,8-diol-9,10-epoxide of benzo[a]pyrene, showed that excision repair prior to the onset of S phase also decreased the frequency of mutants induced in XP variant cells by this agent. But for every dose and time point, the frequencies induced in XP4BE cells and normal cells were identical. Thus, the hypermutability of the XP4BE cells was specific to UV radiation-induced DNA lesions.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1994

Floral variant of follicular lymphoma. Immunological and molecular studies support a neoplastic process.

In recent reports of the so-called "floral variant" of follicular lymphoma, an unusual variant of follicular lymphoma mimicking progressive transformation of germinal centers, questions have been raised regarding whether this process represents a malignant lymphoma. We studied 19 examples of the floral variant of follicular lymphoma and report our light microscopic, immunohistochemical, and molecular diagnostic findings. Morphologic changes consisted of effacement of normal lymph node architecture by follicles composed of atypical lymphocytes. The follicles were surrounded by prominent mantle zones that invaginated irregularly into the follicle centers, often imparting a "floral" appearance. Sufficient material was available for immunophenotypic or genotypic studies in 15 biopsies. Twelve of 15 cases studied by immunohistochemistry demonstrated phenotypes supporting a diagnosis of lymphoma. Five demonstrated light-chain restriction; one was an immunoglobulin-negative B-cell neoplasm; and six, in which only formalin-fixed, paraffin-embedded tissue was available, demonstrated overexpression of the bcl-2 protein. Southern blot analysis revealed evidence of clonal immunoglobulin heavy-chain gene rearrangement in all five cases tested. Overall, 12 of the 15 biopsies studied with these techniques showed immunologic or genotypic support for malignant lymphoma. The results of this study demonstrate that the floral variant of follicular lymphoma does indeed represent a malignant lymphoma.

Adult↗
PubMed1988

Rearrangement of both immunoglobulin and T-cell receptor genes in a prolymphocytic variant of hairy cell leukemia patient resistant to interferon-alpha.

We describe a patient with the so-called "prolymphocytic variant" form of hairy cell leukemia (HCL) resistant to treatment with interferon-alpha (IFN-alpha). Analysis of immunoglobulin (Ig) and T-cell receptor-beta (TCR beta) gene rearrangements from serial peripheral blood mononuclear cell specimens (MNCs) confirmed not only the B-cell nature of the disease, but also the subsequent emergence of a morphologically indistinguishable population of cells with a clonal TCR beta rearrangement in addition to the original Ig gene rearrangement. With the exception of a transient increase in peripheral blood T cells during treatment with deoxycoformycin (DCF), the MNCs remained essentially constant throughout therapy with no evidence of a co-existing T-cell clone to account for the TCR beta rearrangement. Although MNCs from this patient bound significantly less IFN-alpha than did MNCs from other HCL patients, the binding was of high affinity with a kd similar to that of control cells. The number of IFN-gamma receptors on our patient's MNCs was four times higher than the number of IFN-alpha receptors and was similar to the number of IFN-alpha receptors on MNCs from HCL patients responsive to IFN-alpha. While various treatments including IFN-alpha, DCF, chlorambucil, splenectomy, leukopheresis, and IFN-gamma were not able to change the clinical progression of the disease, they may have provided an opportunity for the divergent TCR beta rearranged clone to expand and displace the initially dominant clone.

Aged↗
PubMed1975

'Normal' and 'lesional' traits of personality according to Sjöbring: re-tatings and prognostic implications. The Lundby project.

As a supplement to findings made in two studies of the same rural population with a 10-year interval, the 'reliablity' of various subjective ratings of normal personality was looked into: the variants in validity, solidity, and stability as described by Sjobring. In addition the findings of Hagnell, according to which the above-mentioned normal variants of personality hardly influenced first incidence of mental disorder during the period of observation, while so-called 'lesional' variants did, were further investigated and confirmed.

Adolescent↗
PubMed1994

Allele-specific expression of a variant-specific surface protein (VSP) of Giardia lamblia.

The surfaces of Giardia lamblia trophozoites demonstrate variable expression of a set of cysteine-rich surface proteins, called variant-specific surface proteins (VSP). The cloned Giardia line, WBA6, expresses a 170 kD VSP (VSPA6 or CRP170) which contains approximately 18 to 23 copies of a 65 amino acid repeat. We have cloned the expressed vspA6 gene containing 23 repeats from a genomic library as well as copies of the vspA6 gene with only 8 or 9 repeats from both WBA6 and from WB1269, a cloned line derived from WBA6 which has lost the expressed copy of the gene. The recombinant clones containing the genes with only 8 or 9 repeats have 8 nucleotide substitutions in the coding region. All the recombinant clones map to the same chromosomal location, yet RNA sequencing and comparison with the transcript size indicate that only the clone with 23 repeats contains a gene producing a stable transcript. The most likely interpretation of these data is that G.lamblia trophozoites contain multiple alleles of the vspA6 gene of which only one is expressed.

Alleles↗
PubMed2025

Genome sequencing reveals the impact of pseudoexons in rare genetic disease.

PURPOSE: Advancements in sequencing technologies have significantly improved clinical genetic testing; yet, the diagnostic yield remains around 30% to 40%. Emerging technologies are now being deployed to address the remaining diagnostic gap. METHODS: We tested whether short-read genome sequencing could increase the diagnostic yield in individuals enrolled into the UCI-GREGoR research study, who had suspected Mendelian conditions and prior inconclusive testing. Two other collaborative research cohorts, focused on aortopathy and dilated cardiomyopathy, consisted of individuals who were undiagnosed but had not undergone harmonized prior testing. RESULTS: We sequenced 353 families (754 participants) and found a molecular diagnosis in 54 (15.3%) of them. Of these diagnoses, 55.5% were previously missed because the causative variants were in regions not originally interrogated. In 5 cases, they were deep intronic variants, all of which led to abnormal splicing and pseudoexons, as directly shown by RNA sequencing. All 5 of these variants had inconclusive spliceAI scores. In 26% of newly diagnosed cases, the causal variant could have been detected by exome sequencing reanalysis. CONCLUSION: Genome sequencing can overcome limitations of clinical genetic testing, such as the inability to call intronic variants. Our findings highlight pseudoexons as a common mechanism via which deep intronic variants cause Mendelian disease.

Humans↗