Gene linked to heart defects in Down syndrome identified

2nd February 2024

UK researchers have identified a gene linked to heart defects in Down syndrome (DS), offering a potential therapeutic target for DS-associated congenital heart defects (CHD).

DS, caused by trisomy of human chromosome 21 (Hsa21), resulted in multiple conditions including learning and memory deficits, craniofacial alterations, and CHD, researchers wrote in the journal Science Translational Medicine.

With DS affecting around one in 800 births, it was the most common genetic cause of CHD with around 50% of babies with DS presenting with cardiac defects at birth, the Francis Crick Institute and UCL Institute of Neurology researchers explained.

The most severe defects, such as those affecting the atrioventricular septum, often required surgery in the first years after birth, resulting in substantial morbidity and mortality, they said.

‘This clinically important cardiac pathology is the result of a third copy of one or more of approximately 230 genes on Hsa21, but the identity of the causative dosage-sensitive genes and hence mechanisms underlying this cardiac pathology remain unclear,’ they wrote.

Studying human DS foetal hearts as well as embryonic hearts from a mouse model of DS, they showed they were affected by reduced expression of mitochondrial respiration genes and cell proliferation genes.

Using genetic mapping, they identified one gene on Hsa21 – dual-specificity tyrosine phosphorylation–regulated kinase 1A (Dyrk1a) – which, when present in three copies, was linked with congenital heart disease pathology.

They were also able to show in embryonic hearts from the mouse model of DS, that reducing Dyrk1a gene copy number from three to two reversed defects in cellular proliferation and mitochondrial respiration in cardiomyocytes and rescued heart septation defects.

‘The work presented here shows that mitochondrial dysfunction and reduced cell proliferation correlate with CHDs and that all three of these depend on a third copy of Dyrk1a,’ they wrote.

However, they noted the results did not prove that these cellular changes caused septation defects.

They also noted there was a second unidentified gene at play, with three copies of Dyrk1a necessary, but not sufficient, to cause CHDs.

Eva Lana-Elola, principal laboratory research scientist at the Francis Crick Institute, and study co-first author, said it was remarkable that restoring the copy number of Dyrk1a from three to two reversed the heart defects in the mouse model for DS.

‘We’re now aiming to understand which of the other genes on this extra chromosome are involved,’ she said.

The researchers noted that the Dyrk1a gene encodes for the Dyrk1a protein, and they also tested whether inhibiting this protein’s activity in pregnant mice could reverse CHD changes in the DS mouse model embryos.

For the study, they used the Dyrk1a inhibitor leucettinib-21 at a stage when the mouse pups’ hearts were forming, and they were able to show a partial reversal in genetic changes.

Victor Tybulewicz, group leader of the Immune Cell Biology Laboratory & Down Syndrome Laboratory at the Francis Crick Institute, said the research suggested inhibiting Dyrk1a might be a useful therapeutic approach. 

‘However, in humans the heart forms in the first eight weeks of pregnancy, likely before a baby could be screened for Down syndrome, so this would be too early for treatment,’ he commented.

‘The hope is that a Dyrk1a inhibitor could have an effect on the heart later in pregnancy, or even better after birth.’

The researchers worked with Perha Pharmaceuticals to test the Dyrk1a inhibitor, which is also being trialled for cognitive disorders associated with DS and Alzheimer’s disease.

Rifdat Aoidi, postdoctoral project research scientist at the Francis Crick Institute, and study co-first author, said: ‘We don’t yet know why the changes in cell division and mitochondria mean the heart can’t correctly form chambers.

‘Dysfunction in the mitochondria has also been linked to cognitive impairment in Down syndrome, so boosting mitochondrial function could be another promising avenue for therapy.’

Two genes found to confer multidrug chemoresistance in head and neck cancers

11th September 2023

Two genes appear to be responsible for conferring chemoresistance in the majority of drug-resistant cell strains of patients with head and neck cancers, and silencing either gene leads to a complete reversal of drug resistance, researchers at Queen Mary University of London (QMUL) have found.

In the study, published in the journal Molecular Cancer, the team used transcriptome data-mining to identify potential genes that may be affecting tumour responsiveness to drug therapy. They identified a total of 28 genes in 12 strains of chemoresistant cell lines each against cisplatin, 5-fluorouracil, paclitaxel and docetaxel chemotherapies.

A total of 10 multi-drug chemoresistance genes were identified, four of which – TOP2A, DNMT1, INHBA and NEK2 – were up-regulated in a cohort of 221 head and neck cancer patients.

The INHBA and NEK2 genes appeared to be pan-cancer prognostic markers for predicting poor survival outcome in the majority of cancer types. But the team also identified two compounds – sirodesmin A and carfilzomib – from drug library screens, which were able to target both INHBA and NEK2 and re-sensitise cisplatin-resistant cells.

Dr Muy-Teck Teh, senior author of the study from QMUL, said: ‘These results are a promising step towards cancer patients in the future receiving personalised treatment based on their genes and tumour type that give them a better survival rate and treatment outcome.

‘Unfortunately, there are lots of people out there who do not respond to chemotherapy or radiation. But our study has shown that in head and neck cancers at least it is these two particular genes that could be behind this, which can then be targeted to fight against chemoresistance.‘

In Europe, head and neck cancers affect around 22 people per 100,000. While the cure rate is high for early-stage disease, around two-thirds of patients present with advanced-stage disease with a poor survival outcome. An additional and important cause of treatment failure leading to a poor survival, is the development of resistance to chemo and/or radiotherapy, although the underlying genes responsible for chemoresistance have previously been unclear.

Genes responsible for premature ovarian insufficiency questioned by researchers

6th July 2023

Premature ovarian insufficiency (POI) in the majority of women is not due to autosomal dominant variants in genes, according to a recent analysis.

Published in the journal Nature Medicine, researchers set out to systematically evaluate the penetrance of purported pathogenic gene variants using exome sequence data in women with POI.

They considered 67 genes used in the Genomics England diagnostic gene panel for POI, and identified an additional 38 genes from additional literature.

The team used exome sequence data in 104,733 women from the UK Biobank, 2,231 of whom (1.14%) reported natural menopause under the age of 40 years.

The analysis showed limited evidence to support any previously reported autosomal dominant effect. In fact, for nearly all heterozygous effects on previously reported POI genes, researchers were able to rule out even modest penetrance. For instance, 99.9% of all protein-truncating variants were present in reproductively healthy women.

Taken together, these results suggest that in the vast majority of women, POI is not actually caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels.

In other words, while there are specific genetic variants in women who experience premature menopause, it is unlikely that these variants are the underlying cause, since many are also found in those who experience a normal age menopause.

POI in context

POI affects an estimated 1% of the general population and results in cessation of ovarian function before the age of 40 years. Moreover, women with POI find that menstruation also stops around the same age. In recent years, it has become clear that POI is likely to have a genetic basis and although several candidate genes have been identified, it appears that POI is a genetically heterogeneous condition.