POLR3A variants with striatal involvement and extrapyramidal movement disorder

Biallelic variants in POLR3A cause 4H leukodystrophy, characterized by hypomyelination in combination with cerebellar and pyramidal signs and variable non-neurological manifestations. Basal ganglia are spared in 4H leukodystrophy, and dystonia is not prominent. Three patients with variants in POLR3A, an atypical presentation with dystonia, and MR involvement of putamen and caudate nucleus (striatum) and red nucleus have previously been reported. Genetic, clinical findings and 18 MRI scans from nine patients with homozygous or compound heterozygous POLR3A variants and predominant striatal changes were retrospectively reviewed in order to characterize the striatal variant of POLR3A-associated disease. Prominent extrapyramidal involvement was the predominant clinical sign in all patients. The three youngest children were severely affected with muscle hypotonia, impaired head control, and choreic movements. Presentation of the six older patients was milder. Two brothers diagnosed with juvenile parkinsonism were homozygous for the c.1771-6C > G variant in POLR3A; the other seven either carried c.1771-6C > G (n = 1) or c.1771-7C > G (n = 7) together with another variant (missense, synonymous, or intronic). Striatal T2-hyperintensity and atrophy together with involvement of the superior cerebellar peduncles were characteristic. Additional MRI findings were involvement of dentate nuclei, hila, or peridentate white matter (3, 6, and 4/9), inferior cerebellar peduncles (6/9), red nuclei (2/9), and abnormal myelination of pyramidal and visual tracts (6/9) but no frank hypomyelination. Clinical and MRI findings in patients with a striatal variant of POLR3A-related disease are distinct from 4H leukodystrophy and associated with one of two intronic variants, c.1771-6C > G or c.1771-7C > G, in combination with another POLR3A variant

Heterogeneous ribosome populations are present in Plasmodium berghei during development in its vector

The genome of the rodent malaria parasite, Plasmodium berghei, contains two sets of variant ribosomal RNA (rRNA) genes, termed the A and S types, that are expressed predominantly during the vertebrate and mosquito stages of the parasite's development respectively. Using in situ hybridization, we have examined the transcriptional activity of the A- and S-type rRNA genes, and the switch in expression of the ribosome populations that occurs after parasite transmission to the mosquito. By detection of precursor rRNA molecules, we show that A-type rRNA transcription is downregulated throughout development in the mosquito, whereas the initiation of S-type rRNA transcription is linked to the proliferative phase of the oocyst. Mature A-type rRNA persists during development of the zygote into the ookinete/young oocyst. In contrast, mature S-type rRNA is first detectable in young oocysts and is subsequently present at high levels during further development of oocysts and sporozoites. These results demonstrate that the switch in transcription between the A- and S-type rRNA genes is developmentally regulated, taking place only as the parasite begins to proliferate in the mosquito. A-type ribosomes are therefore not only translationally active in the early stages of development in the mosquito, but are also crucial at this phase

High-resolution mapping of molecular events associated with immortalization, transformation, and progression to breast cancer in the MCF10 model

Background. A comprehensive and consistent picture of the genetic changes that underlie breast cancer initiation, development, and progression remains unresolved. The MCF10 series of cell lines represents many steps in that progression. We performed high resolution mapping of the MCF10 series of cell lines to identify specific gene targets to elucidate the molecular correlates of immortalization, development, and progression of breast cancer at the level of individual genes. Design. We evaluated the initial untransformed outgrowths (MCF-10MS and MCF-10A) with six transformed cell lines with benign proliferations (MCF-10AT1, MCF-10AT1kcl2), carcinoma in situ (MCF-10CA1h cl13), and invasive carcinoma (MCF-10CA1h cl2, MCF-10CA1a cl1, MCF-10CA1d cl1). Losses and gains of loci at 112 unique human genome sites were interrogated using the multiplex ligation-dependent probe amplification assay (MLPA). Results. Cytogenetic alterations in the four benign progenitors that persisted in the CIS and invasive cell lines corresponded to gains and losses of genes by MLPA. MCF-10MS had only normal gene copies. The untransformed MCF-10A had cytogenetic gain of 5q13-qter with corresponding gains of the IL3, IL4 and IL12B genes at 5q31-q33; gain of distal 19q12-qter was reflected in gains in KLK3 and BAX gene loci at 19q13-q13.4. The observed genie gain of cMYC at 8q24.12 was not indicated by cytogenetics. The apparently balanced t(3;9) component of the t(3;9)(p13;p22)t(3;5)(p26;q31) resulted in complete loss of the CDKN2A and CDKN2B genes at 9p21. Additional clonal cytogenetic changes in the DCIS cell line (MCF-10A1h cl13) involving chromosomes 1, 3 and 10 persisted in the invasive progeny, with gain of corresponding genes at 1p13 (BCAR2, BCAR3, NRAS, TGFB2), at 3p12-13 (IL12A), and 3q21-27 (MME, PIK3CA, BCL6). Conclusions. Our study adopted a comprehensive exploration of genetic changes using high resolution molecular probes applied to the MCF10 family of cell lines to identify individual genes in a continuum starting from normal breast epithelial cells and progressing through immortalization, transformation and invasive malignancy. Homozygous loss of CDKN2A and CDKN2B genes and gain of MYC were initiating immortalization events. Transformation and progression to malignancy event were marked by gains of IL13, VEGF, HRAS, TRAF2, and BCAS2, IL12A, and MME, respectively

Congenital amegakaryocytic thrombocytopenia presenting with a new thrombopoietin receptor (MPL) pathogenic variant: An instructive neonatal case

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Interferon-alpha and the calcifying microangiopathy in Aicardi-Goutieres syndrome

Aicardi-Goutieres syndrome is a leukoencephalopathy with calcifications and increased cerebrospinal fluid interferon-alpha. The relation between interferon-alpha and brain pathology is poorly understood. We report a patient with mutations in the disease-associated gene SAMHD1. Neuropathology showed an extensive microangiopathy with calcifications consistently associated with blood vessels. In an in vitro model of the microangiopathy, interferon-alpha enhanced vascular smooth muscle cell-derived calcifications. The noninfarcted white matter harbored apoptotic oligodendrocytes and increased numbers of oligodendrocyte progenitors. These findings better define the white matter pathology and provide evidence that interferon-alpha plays a direct pathogenetic role in the calcifying angiopathy typical of this diseas