bims-actimu 2025-05-18 papers

Blood Coagul Fibrinolysis. 2025 Apr 25.

Haploidentical stem cell transplantation in DOCK8 deficiency: a case report of successful outcomes.

Sondus Alsharidah, Ahmed Elhussein, Waleed Al-Herz.

DOCK8 deficiency syndrome, formerly known as autosomal recessive hyper-IgE syndrome (AR-HIES), is a rare combined immunodeficiency disorder characterized by recurrent infections, eczema, eosinophilia, and elevated immunoglobulin E (IgE) levels. We present a case of a 6-year-old girl with DOCK8 deficiency syndrome, who experienced recurrent skin infections and molluscum contagiosum since infancy. Genetic testing confirmed the diagnosis. Due to the high morbidity and mortality associated with DOCK8 deficiency syndrome, she underwent hematopoietic stem cell transplantation (HSCT) from her father. Posttransplant, the patient's skin condition significantly improved, and she achieved full donor chimerism. This case highlights the importance of considering DOCK8 deficiency in patients with recurrent infections, eczema, eosinophilia, and high IgE levels, and the potential curative effect of HSCT for these patients.

Keywords: DOCK8 deficiency syndrome; curative treatment; eczema; hematopoietic stem cell transplantation; hyper-IgE; recurrent infections

DOI: https://doi.org/10.1097/MBC.0000000000001351

Allergy. 2025 May 10.

Comprehensive αβ T-Cell Receptor Repertoire Analysis Reveals a Unique CD8+ TCR Landscape in DOCK8-Deficient Patients.

BACKGROUND: Dedicator of cytokinesis protein 8 (DOCK8) is a guanine nucleotide exchange factor highly expressed in, and critical for, the function of various innate and adaptive immune cells. DOCK8 deficiency leads to combined immunodeficiency characterized by susceptibility to infections, autoimmunity, and a severe Th2-type immune response. While dysfunction in various T cell subsets has been implicated in these phenotypes, a comprehensive analysis of the T-cell receptor (TCR) repertoire in these patients has not yet been documented. This study investigates the αβ TCR repertoire in DOCK8-deficient patients to identify features related to disease pathogenesis and explore the potential role of TCR repertoire alterations in disease development.
METHODS: We compared immune repertoire profiles determined by high-throughput TCR sequencing of circulating CD4+ and CD8+ T cells from patients with DOCK8 deficiency (n = 10) to healthy controls (n = 7) and patients with ataxia-telangiectasia (AT) (n = 5).
RESULTS: Different diversity analyses revealed a restricted TRA and TRB repertoire in both CD4+ and CD8+ T cells from DOCK8-deficient patients, with the restriction being more pronounced in CD8+ T cells. Skewed usage of individual variable (V) and joining (J) genes and potentially self-reactive CD8+ T cell clones, as determined by hydrophobicity and cysteine indices, were identified in DOCK8-deficient patients.
CONCLUSION: Our study represents the most comprehensive immune repertoire analysis in DOCK8 deficiency. The identification of a significantly restricted αβ TCR repertoire, along with the detection of potentially autoreactive clones, highlights the crucial role of immune repertoire profiling in elucidating the pathogenesis of DOCK8 deficiency.

Keywords: DOCK8 deficiency; T‐cell receptor repertoire; autoimmunity; immune repertoire sequencing

DOI: https://doi.org/10.1111/all.16580

Clin Genet. 2025 May 15.

Case Report: Association of Ocular Colobomas With a Novel Missense Variant in CDC42, a Member of the Rho Family of Small GTPases.

Diana Brightman, Nawaal Shinwari, Aleksey Porollo, Eniolami O Dosunmu, Ehsan Ullah, Bin Guan, Robert B Hufnagel, Brian P Brooks, Delphine Blain, Sabine Fuhrmann, Brittany Simpson, Anne M Slavotinek.

We present a 2-year-old male with bilateral iris and chorioretinal colobomas, speech delays, and facial and digital anomalies. Trio exome sequencing demonstrated a de novo, novel heterozygous variant, c.379G>A p.Glu127Lys in CDC42, conferring a diagnosis of Takenouchi-Kosaki syndrome. The p.Glu127Lys variant was not located in the same region as previously designated mutation classes for CDC42, and the patient's missense substitution was predicted to disrupt CDC42 interactions with Collybistin II and IQGAP1. As conditional knock-out mouse models have demonstrated coloboma in association with loss of Cdc42 expression, we conclude that the colobomas can be attributed to the CDC42 variant and that similar ocular anomalies are likely to be described with other Rho GTPases in the future.

Keywords: CDC42; Cdc42; Takenouchi‐Kosaki syndrome; coloboma

DOI: https://doi.org/10.1111/cge.14768

Nat Commun. 2025 May 14. 16(1): 4491

Inherited deficiency of DIAPH1 identifies a DNA double strand break repair pathway regulated by γ-actin.

DNA double strand break repair (DSBR) represents a fundamental process required to maintain genome stability and prevent the onset of disease. Whilst cell cycle phase and the chromatin context largely dictate which repair pathway is utilised to restore damaged DNA, it has been recently shown that nuclear actin filaments play a major role in clustering DNA breaks to facilitate DSBR by homologous recombination (HR). However, the mechanism with which nuclear actin and the different actin nucleating factors regulate HR is unclear. Interestingly, patients with biallelic mutations in the actin nucleating factor DIAPH1 exhibit a striking overlap of clinical features with the HR deficiency disorders, Nijmegen Breakage Syndrome (NBS) and Warsaw Breakage Syndrome (WABS). This suggests that DIAPH1 may play a role in regulating HR and that some of the clinical deficits associated with DIAPH1 mutations may be caused by an underlying DSBR defect. In keeping with this clinical similarity, we demonstrate that cells from DIAL (DIAPH1 Loss-of-function) Syndrome patients display an HR repair defect comparable to loss of NBS1. Moreover, we show that this DSBR defect is also observed in a subset of patients with Baraitser-Winter Cerebrofrontofacial (BWCFF) syndrome associated with mutations in ACTG1 (γ-actin) but not ACTB (β-actin). Lastly, we demonstrate that DIAPH1 and γ-actin promote HR-dependent repair by facilitating the relocalisation of the MRE11/RAD50/NBS1 complex to sites of DNA breaks to initiate end-resection. Taken together, these data provide a mechanistic explanation for the overlapping clinical symptoms exhibited by patients with DIAL syndrome, BWCFF syndrome and NBS.

DOI: https://doi.org/10.1038/s41467-025-59553-0