Medical oddity results in the invention of outrageous “immunity gene” mutations – and a greater technique to examine them

The strange case of a child with rare encephalitis that does not usually occur in children led researchers to discover never-before-seen genetic mutations and a more accurate technique for studying the IRAK4 gene, which is responsible for innate immunity.

The IRAK4 gene controls the production of a protein that plays a key role in the early detection and response to invading pathogens. Inherited mutations in this gene can cause an immune system disorder, making the body vulnerable to recurring infections with pus-forming pyogenic bacteria. IRAK4 deficiency cases are quite rare and only about 10 familial cases have been identified in Japan.

A research team led by the University of Hiroshima discovered two novel IRAK4 mutations, c.29_30delAT (p.Y10Cfs * 9) and c.35G> C (p.R12P), in a 10-month-old boy with anti-N-methyl encephalitis of the d-aspartate receptor (anti-NMDAR) and reactivation of the human herpes virus 6 (HHV6). The variations p.Y10Cfs * 9 and p.R12P were inherited from his father and mother, respectively. The research team found the mutations using full exome sequencing (WES), a method that extensively examines DNA for genetic disorders.

Anti-NMDAR encephalitis, an inflammation of the brain, occurs when the immune system attacks a vital brain receptor, causing psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation. It typically occurs in adult women who have an ovarian tumor. Few cases of anti-NMDAR encephalitis have been reported in infants to date.

The researchers suspect that reactivation of HHV6 led to brain damage that triggered the production of anti-NMDAR antibodies. Her work was published in the Journal of Clinical Immunology.

It is known that anti-NMDAR encephalitis is caused by HSV1 infection (herpes simplex virus). The autoimmune post-infectious process that follows HSV-induced brain damage is believed to be the cause of anti-NMDAR encephalitis.

The coexistence of anti-NMDAR encephalitis and HHV6 reactivation in this patient may indicate an unknown manifestation associated with IRAK4 deficiency.

With this system we have confirmed that both new mutations are harmful. The current case demonstrated the possibility that genetics can help characterize children’s cases with anti-NMDAR encephalitis.

Hiroshimas Satoshi Okada, co-author of the study.

They solved potential mispricing issues in a previously developed NF-κB reporter assay by using CRISPR gene editing technology to remove the IRAK4 naturally expressed in the HEK293 cell – which is often used to study gene function because it is much easier to transfect than other cell lines.

So far, 24 mutations are known in patients with IRAK4 deficiency. The research team hopes to soon be able to present its novel NF-κB reporter assay system, with the help of which IRAK4 gene mutations can be assessed and an early diagnosis can be achieved.

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