Risk of tumors in Bohring-Opitz Syndrome

Posted by & filed under Part 04: CANCER.

Bohring-Opitz Syndrome (BOS, MIM 612990) is a rare condition characterized by dysmorphic features, failure to thrive, severe intellectual disability,  nevus flammeus and myopia. It can be caused by heterozygous mutations in ASXL1, a gene involved in the regulation of Hox genes.

Russel et al. (AJMG, 2015, Apr 29. doi: 10.1002/ajmg.a.37131. [Epub ahead of print]) just published clinical management recommendations for this condition, including for feeding concerns, vomiting, infection, and other features. They also reported on two BOS patients who developed bilateral Wilms Tumor. As somatic mutations in ASXLI have been previously associated with myeloid malignancies, the increased risk for cancer in BOS patients is not completely unexpected. The authors recommend that patients with BOS undergo kidney ultrasounds every 3-4 months in the first 8 years of life.

Hilary Vernon, MD PhD

Role of GABA Receptors for synaptic plasticity and memory in Down syndrome

Posted by & filed under Part 05: CHROMOSOMES.

Altered GABAergic transmission through Cl-permeable GABAA receptors (GABAARs) is known to contribute to learning and memory deficits in Down syndrome mouse models. In this study, GABAAR signaling was found to be excitatory rather than inhibitory, and the reversal potential for GABAAR-driven Cl currents (ECl) was shifted toward more positive potentials in the hippocampi of adult Down syndrome mice. Hippocampal expression of cation Cl cotransporter NKCC1 was increased in both trisomic mice and individuals with Down syndrome. Notably, NKCC1 inhibition by the FDA-approved drug bumetanide restored ECl, synaptic plasticity and hippocampus-dependent memory in adult Down syndrome mice. Therefore, this paper identifies the excitatory role of GABA in Down syndrome brain and suggests a new approach for therapy of cognitive disabilities in Down syndrome.



Posted by Nicola Brunetti-Pierri

Progress in nanopore technology

Posted by & filed under Exome sequencing, In the news, Part 06: DIAGNOSTIC APPROACHES, Tools.

Feng et al. (2015) recently reviewed the progress in nanopore technology from the past as well as the latest advances. They describe the different types of nanopores and discuss recent and potential applications. Nanopore-based sequencers have the potential to quickly and reliably sequence the entire human genome “for less than $1000, and possibly for even less than $100”. Some significant advantages of nanopores include minimal sample preparation, elimination of the need for amplification or modification (nucleotides, polymerases or ligases), label-free, rapid, ultra-long reads (read lengths of 10,000–50,000 bases), high throughput, and low material requirement.  Among the challenges discussed, single base recognition and slowing down the rate of DNA velocity are still the principal challenges for the nanopore rechnology.

Nanopore-based Fourth-generation DNA Sequencing Technology. Feng Y, Zhang Y, Ying C, Wang D, Du C. Genomics Proteomics Bioinformatics. 2015 Feb;13(1):4-16. Review. PMID:25743089

Posted by Yannis Trakadis, MD

Tissue-based map of the human proteome

Posted by & filed under Tools, Websites.

Ulen et al. used an integrative omics approach to study the spatial human proteome. Samples representing all major tissues and organs in the human body were analyzed based on 24,028 antibodies corresponding to 16,975 protein-encoding genes, complemented with RNA-sequencing data for 32 of the tissues.

A genome-wide analysis of the tissue specificity of RNA and protein expression covering more than 90% of the putative protein-coding genes, complemented with analyses of various subproteomes(e.g. membrane-bound proteins), was performed.

A freely available interactive resource is available at www.proteinatlas.org.

Proteomics. Tissue-based map of the human proteome. Uhlén et al. Science. 2015 Jan 23;347(6220):1260419.


posted by Yannis Trakadis, MD

CRISPR tool (treatment & mutations assessment)

Posted by & filed under Tools, Treatment.

CRISPR-Cas9-based genome editing enables the rapid genetic manipulation of any genomic locus without the need for gene targeting by homologous recombination. It can be used in the search for new treatment modalities, e.g. studies focusing on the identification of physiological targets of drugs and bioactive small molecules (Zhu et al. 2015; Kasap et al 2014). One of the benefits of this approach is that it can help uncover the mechanisms of drug action for existing drugs, thus enabling the trial of other candidate drugs with similar function. More recently, a conditional transgenic approach using CRISPR-Cas9-based genome editing was shown to allow temporal control of CRISPR-Cas9 activity for inducible genome editing in adult mice (via doxycycline-regulated Cas9 induction). This inducible CRISPR (iCRISPR) system can also be used effectively to create biallelic mutation in multiple target loci and, thus, provides a flexible and fast platform to study loss-of-function phenotypes in vivo.

The CRISPR/Cas9 system inactivates latent HIV-1 proviral DNA. Zhu et al. Retrovirology. 2015 Feb 27;12(1):22.  PMID:25808449

DrugTargetSeqR: a genomics- and CRISPR-Cas9-based method to analyze drug targets. Kasap C, Elemento O, Kapoor TM. Nat Chem Biol. 2014 Aug;10(8):626-8. PMID: 24929528

Inducible in vivo genome editing with CRISPR-Cas9. Dow et al. Nat Biotechnol. 2015 Feb 18.  PMID: 25690852

posted by Yannis Trakadis, MD

Mitochondrial metabolism and the circadian clock

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION.

Biochemical consequences in primary inborn errors of metabolism are often clear and predictable (i.e. elevated plasma phenylalanine in phenylalanine hydroxylase deficiency). However, potential biochemical consequences of genetic aberrations that do not have an obvious connection to metabolic pathways are much more difficult to understand.

Kohsaka et al. (PLOS One, 2014 9(11): 1-16) described cardiac mitochondrial abnormalities in a mouse model with cardiac targeted disruption of the circadian clock gene, Bmal1. These abnormalities include decreased expression of genes involved in fatty acid metabolism and the citric acid cycle, pathologic mitochondrial morphology, and defects in mitochondrial dynamics.

Such findings have implications for treatment approaches in disorders of circadian rhythm, and expand our understanding of the role of metabolism in complex phenotypes.

Hilary Vernon, MD PhD

Brain somatic mutations in MTOR cause focal cortical dysplasia and epilepsy

Posted by & filed under Part 28: NEUROGENETICS.

Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. Using deep whole-exome sequencing in paired brain-blood DNA from subjects with FCDII, Lim et al. uncovered brain somatic mutations in mechanistic target of rapamycin (MTOR). The identified mutations induced the hyperactivation of mTOR kinase. Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons. Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures. This study provides the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD.


Posted by Nicola Brunetti-Pierri

Potential therapy for MTO1 abnormalities

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION.

Mitochondrial tRNA modification abnormalities are a recently recognized pathologic mechanism leading to defects in oxidative phosphorylation. Genes involved in these modifications include GTPBP3, and MTO1.

Tischner et al (Hum. Mol. Genet. (2015) 24 (8):2247-2266.doi: 10.1093/hmg/ddu743) recently described experiments with a mouse model for MTO1 deficiency, in which implementation of a ketogenic diet was found to subvert the oxidative phosphorylation defect, with effects on mitochondrial and cellular secondary stress responses. 

It is not clear if this intervention has a role in other disorders of mitochondrial tRNA modification, but this is an area worth further exploration, as there is little other specific therapy for affected patients.

Hilary Vernon, MD PhD


New phenotype associated with phosphoribosyl pyrophosphate synthetase 1 deficiency

Posted by & filed under Exome sequencing, Part 11: PURINES AND PYRIMIDINES.

Al-Maawali A et al. Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders. European Journal of Human Genetics (2015) 23, 310–316.


Phosphoribosyl pyrophosphate synthetase 1 (PRS-1) catalyses the first step of purine synthesis, and several X-linked disorders have been associated with both its deficiency (Arts syndrome, Charcot-Marie-Tooth disease type 5, and X-linked non-syndromic sensorineural deafness) and its superactivity (associated with gouty arthritis and uric acid lithiasis and, in severe forms, with sensorineural deafness, hypotonia and ataxia).

In this study, the authors use whole exome sequencing to identify a loss-of-function mutation in PRPS1, resulting in PRS-1 enzyme deficiency, as a cause of a novel phenotype in two brothers, consisting of intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadriparesis, macular coloboma-like lesions with retinal dystrophy, severe short stature, diabetes insipidus, and white matter abnormalities.  Nucleotide analysis showed nucleotide depletion (and particularly GTP depletion) as a possible pathophysiological mechanism.

Interestingly, both patients had been found to have an elevated maternal serum AFP; also, one patient had orotic aciduria (orotic acid was not measured in the other). The authors hypothesize that the latter finding could be due to the fact that phosphoribosyl pyrophosphate is necessary for the conversion of orotic acid to orotate monophosphate (by orotate phosphoribosyltransferase) during pyrimidine de novo synthesis.

This study expands the clinical spectrum of PRS-1 deficiency, as well as adding to the differential diagnosis of high maternal serum AFP during pregnancy and to that of orotic aciduria – with the caveat, of course, that until a similar phenotype is found with PRS-1 deficiency in an unrelated patient, the possibility that some of the clinical or biochemical features could be due to a different cause cannot be completely ruled out.


A2ML1 mutations are associated with a Noonan-like syndrome

Posted by & filed under Exome sequencing, Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT.

Vissers L et al. Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome. European Journal of Human Genetics (2015) 23, 317-324.


For a quarter of patients clinically diagnosed with Noonan syndrome, the molecular cause cannot be identified. Through exome sequencing in a case-parent trio, followed by targeted resequencing in 155 patients and functional confirmation of pathogenicity in zebrafish, Vissers et al. identify mutations in A2ML1 as a cause of a Noonan-like disorder with a wide spectrum of severity.

The authors note that A2ML1 is a protease inhibitor that binds to the LRP1 receptor, which in turn directly interacts with CBL and is also an upstream activator of the MAPK/ERK cascade. They therefore speculate that A2ML1 may function upstream of the signalling pathways involved in Noonan syndrome. Perplexingly, expression of A2ML1 mutations did not lead to detectable RAS/MAPK activation in vitro. The authors suggest that this may either be a function of the cell types used in their study, or a true reflection of the fact that the effects of A2ML1 mutations are not mediated by the MAPK/ERK cascade.

This study adds one more gene to the list of possible causes of Noonan syndrome. As the first report of mutations in a gene encoding an extracellular cofactor causing a Noonan-like syndrome, it also suggests a direction for further studies of the complex molecular pathophysiology underlying this disorder.