Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration.

BACKGROUND: TRPM4 is a broadly expressed, calcium-activated, monovalent cation channel that regulates immune cell function in mice and cell lines. Clinically, however, partial loss- or gain-of-function mutations in TRPM4 lead to arrhythmia and heart disease, with no documentation of immunologic disorders. OBJECTIVE: To characterize functional cellular mechanisms underlying the immune dysregulation phenotype in a proband with a mutated TRPM4 gene. METHODS: We employed a combination of biochemical, cell biological, imaging, omics analyses, flow cytometry, and gene editing approaches. RESULTS: We report the first human cases to our knowledge with complete loss of the TRPM4 channel, leading to immune dysregulation with frequent bacterial and fungal infections. Single-cell and bulk RNA sequencing point to altered expression of genes affecting cell migration, specifically in monocytes. Inhibition of TRPM4 in T cells and the THP-1 monocyte cell line reduces migration. More importantly, primary T cells and monocytes from TRPM4 patients migrate poorly. Finally, CRISPR knockout of TRPM4 in THP-1 cells greatly reduces their migration potential. CONCLUSION: Our results demonstrate that TRPM4 plays a critical role in regulating immune cell migration, leading to increased susceptibility to infections.

Acute Myeloid Leukemia Presenting with Numb Chin Syndrome: A Case Report and Review of Literature.

BACKGROUND Numb chin syndrome is a rare and under diagnosed neuropathy of the inferior alveolar branch of the trigeminal nerve usually causing a lower lip and chin anesthesia or paresthesia. The syndrome is commonly associated with broad-spectrum malignant and non-malignant conditions. CASE REPORT Here we report a case of a 30-year-old male who presented with numb chin syndrome in the form of jaw pain, paresthesia, and hypoesthesia of the mental area as the presenting symptoms of acute of myeloid leukemia with t(8;21) treated with (3+7) protocol (3 days anthracycline+7 days cytarabine). The pain and paresthesia improved but hypothesia persisted. CONCLUSIONS Acute myeloid leukemia is one of the most serious causes of numb chin syndrome which should not be overlooked.

A Novel STAT3 Mutation in a Qatari Patient With Hyper-IgE Syndrome.

Autosomal dominant hyper-IgE syndrome caused by mutations in the transcription factor STAT3 (AD-HIES) is characterized by a collection of immunologic and non-immune features including eczema, recurrent infections, elevated IgE levels, and connective tissue anomalies. We report the case of a Qatari child with a history of recurrent staphylococcal skin infections since infancy, who was found to have a novel, de novo mutation in STAT3 (c.1934T>A, p.L645Q). The absence of mucocutaneous candidiasis and undetectable IgE levels until the age of 7 years prolonged the time to molecular confirmation of the cause for the patient's immune deficiency. STAT3 p.L645Q was found to have decreased transcriptional capacity. The patient also had low levels of Th17 cells and STAT3 phosphorylation was impaired in patient-derived cells. Nearly 100 unique mutations in STAT3 have been reported in association with AD-HIES.