Response to phenotypic hetergeneity of POMT2 variants

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Clinical and cytogenomic findings in OAV spectrum

The oculoauriculovertebral spectrum (OAVS) is characterized by anomalies involving the development of the first and second pharyngeal arches during the embryonic period. The phenotype is highly heterogeneous, involving ears, eyes, face, neck, and other systems and organs. There is no agreement in the literature for the minimum phenotypic inclusion criteria, but the primary phenotype involves hemifacial microsomia with facial asymmetry and microtia. Most cases are sporadic and the etiology of this syndrome is not well known. Environmental factors, family cases that demonstrate Mendelian inheritance, such as preauricular appendages, microtia, mandibular hypoplasia, and facial asymmetry; chromosomal abnormalities and some candidate genes suggest a multifactorial inheritance model. We evaluated clinical, cytogenomic and molecularly 72 patients with OAVS, and compared our findings with patients from the literature. We found 15 CNVs (copy number variations) considered pathogenic or possibly pathogenic in 13 out of 72 patients. Our results did not indicated a single candidate genomic region, but recurrent chromosomal imbalances were observed in chromosome 4 and 22, in regions containing genes relevant to the OAVS phenotype or related to known OMIM diseases suggesting different pathogenic mechanisms involved in this genetically and phenotypic heterogeneous spectrum.

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JNA Journal Club

No abstract available

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A calcium optimum for cytotoxic T lymphocyte and natural killer cell cytotoxicity

Abstract

Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are required to protect the human body against cancer. Ca²⁺ is a key metabolic factor for lymphocyte function and cancer homeostasis. We analysed the Ca²⁺ dependence of CTL and NK cell cytotoxicity against cancer cells and found that CTL have a bell-shaped Ca²⁺ dependence with an optimum for cancer cell elimination at rather low [Ca²⁺]_ext (23–630 μm) and [Ca²⁺]_int (122–334 nm). This finding predicts that a partial inhibition of Orai1 should increase (rather than decrease) cytotoxicity of CTL at [Ca²⁺]_ext higher than 630 μm. We tested this hypothesis in CTL and indeed found that partial down-regulation of Orai1 by siRNA increases the efficiency of cancer cell killing. We found two mechanisms that may account for the Ca²⁺ optimum of cancer cell killing: 1) Migration velocity and persistence have a moderate optimum between 500 and 1000 μm [Ca²⁺]_ext in CTL, and 2) lytic granule release at the immune synapse between CTL and cancer cells is increased at 146 μm comparted to 3 or 800 μm, compatible with the Ca²⁺ optimum for cancer cell killing. It has been demonstrated in many cancer cell types that Orai1-dependent Ca²⁺ signals enhance proliferation. We propose that a decrease of [Ca²⁺]_ext or partial inhibition of Orai1 activity by selective blockers in the tumor microenvironment could efficiently reduce cancer growth by simultaneously increasing CTL and NK cell cytotoxicity and decreasing cancer cell proliferation.

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Intellectual developmental disorder with cardiac arrhythmia syndrome in a child with compound heterozygous GNB5 variants

Identification of a novel compound heterozygous of GNB5 in a patient with intellectual developmental disorder with cardiac arrhytmia (IDDCA), from non-consaguineous family. Three-dimensional modelling and in silico predictions suggest that GNB5 variants are causative of the phenotype, extending the number of IDDCA patients so far identified.

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{-}{-}{-}Pleiotropic Functions of the Chromodomain-Containing Protein Hat-trick During Oogenesis in Drosophila melanogaster

Chromatin-remodeling proteins play a profound role in the transcriptional regulation of gene expression during development. Here, we have shown that the chromodomain-containing protein Hat-trick is predominantly expressed within ­­­­the oocyte nucleus, specifically within the heterochromatinized karyosome and that a mild expression is observed in follicle cells. Co-localization of Hat-trick with Heterochromatin Protein 1 and a Synaptonemal Complex component- C(3)G along with the diffused karyosome after hat-trick down-regulation shows the role of this protein in heterochromatin clustering and karyosome maintenance. Germline mosaic analysis reveals that hat-trick is required for maintaining the dorso-ventral patterning of eggs by regulating the expression of Gurken. The increased incidence of Double strand breaks (DSBs), delayed DSB repair, defects in karyosome formation, altered Vasa mobility and consequently misexpression and altered localization of Gurken in hat-trick mutant egg chambers, clearly suggest a putative involvement of Hat-trick in the early stages of oogenesis. In addition, based on phenotypic observations in hat-trick mutant egg chambers, we speculate a substantial role of hat-trick in cystoblast proliferation, oocyte determination, nurse cell endoreplication, germ cell positioning, cyst encapsulation, and nurse cell migration. Our results demonstrate that hat-trick has profound pleiotropic functions during oogenesis in Drosophila melanogaster.

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Systematic Functional Characterization of Human 21st Chromosome Orthologs in Caenorhabditis elegans

Individuals with Down syndrome have neurological and muscle impairments due to an additional copy of the human 21^st chromosome (HSA21). Only a few of ~200 HSA21 genes encoding protein have been linked to specific Down syndrome phenotypes, while the remainder are understudied. To identify poorly characterized HSA21 genes required for nervous system function, we studied behavioral phenotypes caused by loss-of-function mutations in conserved HSA21 orthologs in the nematode Caenorhabditis elegans. We identified ten HSA21 orthologs that are required for neuromuscular behaviors: cle-1 (COL18A1), cysl-2 (CBS), dnsn-1 (DONSON), eva-1 (EVA1C), mtq-2 (N6ATM1), ncam-1 (NCAM2), pad-2 (POFUT2), pdxk-1 (PDXK), rnt-1 (RUNX1), and unc-26 (SYNJ1).  We also found that three of these genes are required for normal release of the neurotransmitter acetylcholine. This includes a known synaptic gene unc-26 (SYNJ1), as well as uncharacterized genes pdxk-1 (PDXK) and mtq-2 (N6ATM1). As the first systematic functional analysis of HSA21 orthologs, this study may serve as a platform to understand genes that underlie phenotypes associated with Down syndrome.

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