Biomedical subjects

Andrew P Jackson

Publications and source records attributed to Andrew P Jackson.

16 recordsLinked to original sources

PubMed2026

RNU4ATAC-opathy: Clinical, molecular, and transcriptomic insights from a large cohort.

PURPOSE: We aim to better define the genotype and phenotype spectrum of RNU4ATAC-opathy, demonstrate the utility of RNA sequencing (RNA-seq) for variant classification, and highlight the challenges in detecting variants in this noncoding gene. METHODS: Sixty individuals with molecularly confirmed RNU4ATAC-opathy were recruited from multiple clinical and research centers internationally. RNA-seq was available for 7 affected individuals. RESULTS: We report the clinical and molecular findings of 60 individuals, including 42 not previously described, and 33 distinct RNU4ATAC variants, 13 of which are novel. Core features in this cohort-present in most individuals assessed and varying in severity-include microcephaly, short stature, skeletal anomalies, developmental delay, cerebral anomalies, skin conditions, and immune deficiency. Additional findings, such as diabetes, holoprosencephaly, and the absence of various core features in some individuals, highlight the broad phenotypic spectrum. All individuals who underwent RNA-seq showed a consistent pattern of minor intron retention. In 6 individuals, RNA-seq enabled the reclassification of variants of uncertain significance as likely pathogenic. Although RNU4ATAC variants are generally covered by clinical exomes, they are often overlooked in analysis because of their noncoding nature. CONCLUSION: This study highlights the variability of phenotypes and genotypes associated with RNU4ATAC-opathy. Laboratories should ensure RNU4ATAC and other noncoding genes are appropriately assessed by their analysis pipelines.

Lowry-Wood syndrome↗

PubMed2006

Evolution of tubulin gene arrays in Trypanosomatid parasites: genomic restructuring in Leishmania.

BACKGROUND: alpha- and beta-tubulin are fundamental components of the eukaryotic cytoskeleton and cell division machinery. While overall tubulin expression is carefully controlled, most eukaryotes express multiple tubulin genes in specific regulatory or developmental contexts. The genomes of the human parasites Trypanosoma brucei and Leishmania major reveal that these unicellular kinetoplastids possess arrays of tandem-duplicated tubulin genes, but with differences in organisation. While L. major possesses monotypic alpha and beta arrays in trans, an array of alternating alpha- and beta tubulin genes occurs in T. brucei. Polycistronic transcription in these organisms makes the chromosomal arrangement of tubulin genes important with respect to gene expression. RESULTS: We investigated the genomic architecture of tubulin tandem arrays among these parasites, establishing which character state is derived, and the timing of character transition. Tubulin loci in T. brucei and L. major were compared to examine the relationship between the two character states. Intergenic regions between tubulin genes were sequenced from several trypanosomatids and related, non-parasitic bodonids to identify the ancestral state. Evidence of alternating arrays was found among non-parasitic kinetoplastids and all Trypanosoma spp.; monotypic arrays were confirmed in all Leishmania spp. and close relatives. CONCLUSION: Alternating and monotypic tubulin arrays were found to be mutually exclusive through comparison of genome sequences. The presence of alternating gene arrays in non-parasitic kinetoplastids confirmed that separate, monotypic arrays are the derived state and evolved through genomic restructuring in the lineage leading to Leishmania. This fundamental reorganisation accounted for the dissimilar genomic architectures of T. brucei and L. major tubulin repertoires.

Animals↗

PubMed2006

Microcephalin: a causal link between impaired damage response signalling and microcephaly.

Seckel Syndrome (SS) and Primary Microcephaly (MCPH) are disorders exhibiting marked microcephaly with a head circumference less than three standard deviations below the mean. ATR-Seckel Syndrome is conferred by mutations in ataxia and telangiectasia and Rad3 related (ATR), a kinase that activates a DNA damage signalling response. Cell lines from additional SS patients, who are normal for ATR, show defective ATR signalling, suggesting that they carry mutations in other components of the ATR pathway. Primary Microcephaly is distinct from SS since patients display solely microcephaly without accompanying marked growth delay. MCPH1, the first Primary Microcephaly causative gene identified, encodes three BRCT domains, similar to other damage response proteins. Recent studies employing MCPH1 siRNA or exploiting cell lines from MCPH1 patients have shown that MCPH1 functions in the ATR-dependent DNA damage response pathway. Additionally, MCPH1 has a function in the regulation of mitotic entry that is ATR-independent and confers a characteristic phenotype of premature chromosome condensation. Recent studies will be reviewed and their relationship to the aetiology of microcephaly discussed.

Ataxia Telangiectasia Mutated Proteins↗

PubMed2006

Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection.

Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.

Amino Acid Sequence↗

PubMed2006

Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus.

Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1(-/-) mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.

Animals↗

PubMed2006

What primary microcephaly can tell us about brain growth.

Autosomal recessive primary microcephaly (MCPH) is a neuro-developmental disorder that causes a great reduction in brain growth in utero. MCPH is hypothesized to be a primary disorder of neurogenic mitosis, leading to reduced neuron number. Hence, MCPH proteins are likely to be important components of cellular pathways regulating human brain size. At least six genes can cause this disorder and four of these have recently been identified: autosomal recessive primary microcephaly 1 (MCPH1), abnormal spindle-like, microcephaly associated (ASPM), cyclin-dependent kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) and centromere protein J (CENPJ). Whereas aberration of ASPM is the most common cause of MCPH, MCPH1 patients can be more readily diagnosed by the finding of increased numbers of "prophase-like cells" on routine cytogenetic investigation. Three MCPH proteins are centrosomal components but have apparently diverse roles that affect mitosis. There is accumulating evidence that evolutionary changes to the MCPH genes have contributed to the large brain size seen in primates, particularly humans. The aim of this article is to review what has been learnt about the rare condition primary microcephaly and the information this provides about normal brain growth.

Animals↗

PubMed2006

Regulation of mitotic entry by microcephalin and its overlap with ATR signalling.

Ataxia-telangiectasia mutated and Rad3 related (ATR)-Seckel syndrome and autosomal recessive primary microcephaly (MCPH) syndrome share clinical features. RNA interference (RNAi) of MCPH1 have implicated the protein it encodes as a DNA-damage response protein that regulates the transcription of Chk1 and BRCA1, two genes involved in the response to DNA damage. Here, we report that truncating mutations observed in MCPH-syndrome patients do not impact on Chk1 or BRCA1 expression or early ATR-dependent damage-induced phosphorylation events. However, like ATR-Seckel syndrome cells, MCPH1-mutant cell lines show defective G2-M checkpoint arrest and nuclear fragmentation after DNA damage, and contain supernumerary mitotic centrosomes. MCPH1-mutant and ATR-Seckel cells also show impaired degradation of Cdc25A and fail to inhibit Cdc45 loading onto chromatin after replication arrest. Additionally, microcephalin interacts with Chk1. We conclude that MCPH1 has a function downstream of Chk1 in the ATR-signalling pathway. In contrast with ATR-Seckel syndrome cells, MCPH1-mutant cells have low levels of Tyr 15-phosphorylated Cdk1 (pY15-Cdk1) in S and G2 phases, which correlates with an elevated frequency of G2-like cells displaying premature chromosome condensation (PCC). Thus, MCPH1 also has an ATR-independent role in maintaining inhibitory Cdk1 phosphorylation, which prevents premature entry into mitosis.

Ataxia Telangiectasia Mutated Proteins↗

PubMed2006

Comparative genomics and concerted evolution of beta-tubulin paralogs in Leishmania spp.

BACKGROUND: Tubulin isotypes and expression patterns are highly regulated in diverse organisms. The genome sequence of the protozoan parasite Leishmania major contains three distinct beta-tubulin loci. To investigate the diversity of beta-tubulin genes, we have compared the published genome sequence to draft genome sequences of two further species L. infantum and L. braziliensis. Untranscribed regions and coding sequences for each isoform were compared within and between species in relation to the known diversity of beta-tubulin transcripts in Leishmania spp. RESULTS: All three beta-tubulin loci were present in L. infantum and L. braziliensis, showing conserved synteny with the L. major sequence, hence confirming that these loci are paralogous. Flanking regions suggested that the chromosome 21 locus is an amastigote-specific isoform and more closely related (either structurally or functionally) to the chromosome 33 'array' locus than the chromosome 8 locus. A phylogenetic network of all isoforms indicated that paralogs from L. braziliensis and L. mexicana were monophyletic, rather than clustering by locus. CONCLUSION: L. braziliensis and L. mexicana sequences appeared more similar to each other than each did to its closest relative in another species; this indicates that these sequences have evolved convergently in each species, perhaps through ectopic gene conversion; a process not yet evident among the more recently derived L. major and L. infantum isoforms. The distinctive non-coding regions of each beta-tubulin locus showed that it is the regulatory regions of these loci that have evolved most during the diversification of these genes in Leishmania, while the coding regions have been conserved and concerted. The various loci in Leishmania satisfy a need for innovative expression of beta-tubulin, rather than elaboration of its structural role.

3' Flanking Region↗

PubMed2005

The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype.

Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by mental retardation and congenital microcephaly with a head circumference at least 4 SD below age and sex means, in the absence of other significant malformations or neurological deficits. Truncating alterations in the MCPH1 gene have previously been shown to exhibit a distinct cellular phenotype, with a high proportion of prophase-like cells (>10%) due to premature chromosome condensation in early G2- and delayed decondensation in early G1-phase of the cell cycle. We report here the first patient with a homozygous substitution of a highly conserved threonine residue by an arginine (c.80C>G, Thr27Arg) localized in the N-terminal BRCT domain of MCPH1. The cellular and clinical phenotype of this patient is much less pronounced than that of previously described patients with truncating alterations in the MCPH1 gene. Firstly, the fraction of prophase-like cells accounts for just 3-4% of the cell population. Secondly, clinically, he has only a very mild mental retardation with predominantly delayed motor skills but normal verbal IQ attainment. Additionally, head circumference was less severely affected, being -2.4 SD at birth and -3 SD at the age of six years. This justifies reconsideration and widening of the clinical phenotype definition of MCPH1.

Amino Acid Sequence↗

PubMed2005

Evolution of primary microcephaly genes and the enlargement of primate brains.

Brain size, in relation to body size, has varied markedly during the evolution of mammals. In particular, a large cerebral cortex is a feature that distinguishes humans from our fellow primates. Such anatomical changes must have a basis in genetic alterations, but the molecular processes involved have yet to be defined. However, recent advances from the cloning of two human disease genes promise to make inroads in this important area. Microcephalin (MCPH1) and Abnormal spindle-like microcephaly associated (ASPM) are genes mutated in primary microcephaly, a human neurodevelopmental disorder. In this 'atavistic' condition, brain size is reduced in volume to a size comparable with that of early hominids. Hence, it has been proposed that these genes evolved adaptively with increasing primate brain size. Subsequent studies have lent weight to this hypothesis by showing that both genes have undergone positive selection during great ape evolution. Further functional characterisation of their proteins will contribute to an understanding of the molecular and evolutionary processes that have determined human brain size.

Animals↗

PubMed2005

Monocarboxylate transporter MCT1 is a target for immunosuppression.

Current immunosuppressive therapies act on T lymphocytes by modulation of cytokine production, modulation of signaling pathways or by inhibition of the enzymes of nucleotide biosynthesis. We have identified a previously unknown series of immunomodulatory compounds that potently inhibit human and rat T lymphocyte proliferation in vitro and in vivo in immune-mediated animal models of disease, acting by a novel mechanism. Here we identify the target of these compounds, the monocarboxylate transporter MCT1 (SLC16A1), using a strategy of photoaffinity labeling and proteomic characterization. We show that inhibition of MCT1 during T lymphocyte activation results in selective and profound inhibition of the extremely rapid phase of T cell division essential for an effective immune response. MCT1 activity, however, is not required for many stages of lymphocyte activation, such as cytokine production, or for most normal physiological functions. By pursuing a chemistry-led target identification strategy, we have discovered that MCT1 is a previously unknown target for immunosuppressive therapy and have uncovered an unsuspected role for MCT1 in immune biology.

Animals↗

PubMed2004

Mutations in microcephalin cause aberrant regulation of chromosome condensation.

Microcephalin (MCPH1) is a gene mutated in primary microcephaly, an autosomal recessive neurodevelopmental disorder in which there is a marked reduction in brain size. PCC syndrome is a recently described disorder of microcephaly, short stature, and misregulated chromosome condensation. Here, we report the finding that MCPH1 primary microcephaly and PCC syndrome are allelic disorders, both having mutations in the MCPH1 gene. The two conditions share a common cellular phenotype of premature chromosome condensation in the early G2 phase of the cell cycle, which, therefore, appears to be a useful diagnostic marker for individuals with MCPH1 gene mutations. We demonstrate that an siRNA-mediated depletion of MCPH1 is sufficient to reproduce this phenotype and also show that MCPH1-deficient cells exhibit delayed decondensation postmitosis. These findings implicate microcephalin as a novel regulator of chromosome condensation and link the apparently disparate fields of neurogenesis and chromosome biology. Further characterization of MCPH1 is thus likely to lead to fundamental insights into both the regulation of chromosome condensation and neurodevelopment.

Animals↗

PubMed2004

Cophylogeny of the Ficus microcosm.

The various mutualistic and antagonistic symbioses between fig trees (Ficus: Moraceae) and chalcid wasps comprise a community in microcosm. Phylogenetic estimates of figs and fig wasps show general topological correspondence, making the microcosm a model system for cophylogeny. Incongruence between phylogenies from associated organisms can be reconciled through a combination of evolutionary events. Cophylogeny mapping reconciles phylogenies by embedding an associate tree into a host tree, finding the optimal combinations of events capable of explaining incongruence and evaluating the level of codivergence. This review addresses the results of cophylogeny analysis concerning Ficus and discusses the plausibility of different evolutionary events. Five different associations encompassing fig-pollinator, fig-parasite and pollinator-parasitoid interactions are reconciled. The method improves on previous comparisons by employing 'jungles' to provide an exhaustive and quantitative analysis of cophylogeny. A jungle is a mechanism for inferring host switches and obtaining all potentially optimal solutions to the reconciliation problem. The results support the consensus that figs codiverge significantly with pollinators but not non-pollinators. However, pollinators still appear to have switched between hosts in contradiction to the traditional model of faithful codivergence. This emphasises the growing realisation that evolutionary transitions in the microcosm are more flexible than previously thought and host specificity is necessary but not sufficient for codivergence. The importance of sampling strategy is emphasised by the influence of taxon set on the fig-pollinator and fig-parasite jungles. Spurious significant results for fig-parasite and fig-parasitoid jungles indicate that the choice of congruence measure influences significance; the total number of events required to reconcile two trees ('total cost') is not a good measure of congruence when switches cannot be realistically weighted.

Animals↗

PubMed2004

A reconciliation analysis of host switching in plant-fungal symbioses.

Plant-fungal symbioses include many familiar antagonistic and mutualistic associations and some model cases of coevolution. The relationship between coevolution at the different evolutionary scales has remained an open question. Widespread host specificity and documented host switches offer conflicting indications of what to expect from comparisons of plant and fungal phylogenies. This study sought to establish the role of plant phylogeny in determining fungal phylogeny and the relative contributions of codivergence and host switching by comparing tree topologies for 15 plant-fungal symbioses. Second it attempted to characterize the relationship between phylogenetic congruence and switching. Trees were estimated from published sequences and reconciliation analysis was applied in the form of cophylogeny mapping using "jungles". This provided an exhaustive account of all possible switches capable of reconciling two associated phylogenies. A continuum of cophylogenetic dynamics was identified, ranging from mostly codivergence (e.g., Exobasidium) to mostly switching, (e.g., Erysiphe). Surprisingly, congruent solutions do not necessarily have fewer switches when using cophylogeny mapping, but a significant negative relationship between congruence and the distance of switches proved to be a useful indicator. According to reconciliation analysis, the contribution of host phylogeny varies widely across plant-fungal symbioses, making host specificity and coadaptation poor indicators of macroevolutionary trends because they are necessary, but not sufficient, conditions.

Computational Biology↗

PubMed2003

A cophylogenetic perspective of RNA-virus evolution.

The extent to which viruses and their hosts codiverge remains an open question, given that numerous cases of both "cospeciation" and horizontal switching have recently been documented. DNA viruses that form persistent infections are thought to be the most likely candidates for phylogenetic congruence. Phylogenetic reconciliation analysis was used to compare established phylogenies for four RNA viruses and their hosts. The analysis employs a cophylogeny mapping technique, implemented in TreeMap v2.0, to find the most parsimonious combinations of evolutionary events able to reconcile any incongruence. This technique is guaranteed to recover all potentially optimal solutions to the reconciled tree and specifically tests the null hypothesis that an associate phylogeny is no more congruent with a host phylogeny than would be a random tree with the same taxon set. Phylogenies for Hantavirus, Spumavirus, and avian sarcoma leukosis virus were found to be significantly similar to their host trees, whereas Lyssavirus and Arenavirus displayed no significant congruence. These results demonstrate that RNA viruses are able to form stable associations with their hosts over evolutionary time scales and that the details of such associations are consistent with persistent infection being a necessary but not sufficient precondition.

Animals↗

PubMed2002

Identification of microcephalin, a protein implicated in determining the size of the human brain.

Primary microcephaly (MIM 251200) is an autosomal recessive neurodevelopmental condition in which there is a global reduction in cerebral cortex volume, to a size comparable with that of early hominids. We previously mapped the MCPH1 locus, for primary microcephaly, to chromosome 8p23, and here we report that a gene within this interval, encoding a BRCA1 C-terminal domain-containing protein, is mutated in MCPH1 families sharing an ancestral 8p23 haplotype. This gene, microcephalin, is expressed in the developing cerebral cortex of the fetal brain. Further study of this and related genes may provide important new insights into neocortical development and evolution.

Adolescent↗