Malevolent Designer News - How Creationism's Divine Malevolence Capriciously Choses Random Victims

Malevolent Designer News

How Creationism's Divine Malevolence Capriciously choses Random Victims

Study reveals new genetic disorder that causes susceptibility to opportunistic infections | VUMC Reporter | Vanderbilt University

Creationists are obliged by the dogma of their cult to believe that nothing in genetics happens by chance, so everything about an individual’s genetic makeup is the deliberate creation of their putative designer. Indeed, this creator choses the exact sperm that will fertilise the ovum to produce the intended individual complete with the precise genetic makeup of that individual, including any mutations that arise in the creation of the sperm and ovum.

So it must come as something of a shock to creationists to discover that their putative creator appear to randomly create individuals with genes that predispose them to genetic defects and illnesses that mean they will inevitably suffer through no fault of their own, and apparently regardless of how they have lived their lives. In fact, since these are inherited at conception, the predisposition must be at the capricious will of the creator of it.

One such genetic condition was recently discovered by an international team of researchers co-led by immunogeneticist Rubén Martínez-Barricarte from Vanderbilt University Medical Center who have discovered a new genetic disorder that causes immunodeficiency and profound susceptibility to opportunistic infections including a life-threatening fungal pneumonia.
The consortium's finding is reported, open access, in Science Immunology.

According to a news release by Bill Snyder of Vanderbilt University:

The discovery, reported Jan. 20 in the journal Science Immunology, will help identify people who carry this in-born error of immunity (IEI).

Our findings will provide the basis for genetic diagnosis and preventive treatment for these groups of patients.

Martínez-Barricarte, co-senior author Division of Genetic Medicine
Department of Medicine
Vanderbilt Genetics Institute
Vanderbilt University Medical Center, Nashville, TN, USA

IEIs, also known as primary immunodeficiencies, are genetic defects characterized by increased susceptibility to infectious diseases, autoimmunity, anti-inflammatory disorders, allergy, and in some cases, cancer.

To date, 485 different IEIs have been identified. It is now thought that they occur in one of every 1,000 to 5,000 births, making them as prevalent as other genetic disorders, including cystic fibrosis and Duchene’s muscular dystrophy.

Despite recent medical advances, about half of patients with IEIs still lack a genetic diagnosis that could help them avoid debilitating illness and death. That’s why this research is so important.

The error in this case is a mutation in the gene for the protein IRF4, a transcription factor that is pivotal for the development and function of B and T white blood cells, as well as other immune cells.

As a postdoctoral fellow at The Rockefeller University, Martínez-Barricarte was part of an international research team that, in 2018, identified an IRF4 mutation associated with Whipple’s disease, a rare bacterial infection of the intestine that causes diarrhea, weight loss, and abdominal and joint pain.

[…]

Martínez-Barricarte and his team sequenced the protein-encoding regions of the boy’s genome and discovered a de novo IRF4 mutation, which originated in the patient and was not inherited from his parents.

Upon consulting with IRF4 experts at the Imagine Institute for the study and treatment of genetic diseases in Paris, they were told that seven other groups were independently characterizing the same mutation. They now collaborate as the IRF4 International Consortium.

In the current study, the consortium identified seven patients from six unrelated families across four continents with profound combination immunodeficiency who experienced recurrent and serious infections, including pneumonia caused by the fungus Pneumocystis jirovecii. Each patient had the same mutation in the DNA-binding domain of IRF4.

Extensive phenotyping of patients’ blood cells revealed immune cell abnormalities associated with the disease, including impaired maturation of antibody-producing B cells, and reduced T-cell production of infection-fighting cytokines.

Two knock-in mouse models, in which the mutation was inserted into the mouse genome, exhibited a severe defect in antibody production consistent with the combined immune deficiency observed in the patients.

The researchers also discovered the mutation had a “multimorphic” effect detrimental to the activation and differentiation of immune cells.

While the mutant IRF4 binds to DNA with a higher affinity than the native form of the protein (in a hypermorphic way), its transcriptional activity in common, canonical genes is reduced (hypomorphic), and it binds to other DNA sites (in a neomorphic way), altering the protein’s normal gene expression profile.

This multimorphic activity is a new mechanism for human disease.

We anticipate that variants with multimorphic activity may be more widespread in health and disease,

the researchers concluded.

Technical details are given in the team's paper in Science Immunology":

Abstract

Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) and key regulator of immune cell development and function. We report a recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) in seven patients from six unrelated families. The patients exhibited profound susceptibility to opportunistic infections, notably Pneumocystis jirovecii, and presented with agammaglobulinemia. Patients’ B cells showed impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation, whereas their T cells contained reduced T_H17 and T_FH populations and exhibited decreased cytokine production. A knock-in mouse model of heterozygous T95R showed a severe defect in antibody production both at the steady state and after immunization with different types of antigens, consistent with the CID observed in these patients. The IRF4^T95R variant maps to the TF’s DNA binding domain, alters its canonical DNA binding specificities, and results in a simultaneous multimorphic combination of loss, gain, and new functions for IRF4. IRF4^T95R behaved as a gain-of-function hypermorph by binding to DNA with higher affinity than IRF4^WT. Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, showcasing a hypomorphic activity of IRF4^T95R. Simultaneously, IRF4^T95R functions as a neomorph by binding to noncanonical DNA sites to alter the gene expression profile, including the transcription of genes exclusively induced by IRF4^T95R but not by IRF4^WT. This previously undescribed multimorphic IRF4 pathophysiology disrupts normal lymphocyte biology, causing human disease.

Perhaps a victim of the Intelligent [sic] Design hoax would care to suggest a reason their putative divine creator would randomly victimise people this way. Or maybe they'd prefer to ignore the evidence of it's malevolence as usual…

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