PDF(Pubmed)
Abstract：
The transcription factor FOXN1 plays an established role in thymic epithelial development to mediate selection of maturing thymocytes. Patients with heterozygous loss-of-function FOXN1 variants are associated with T cell lymphopenia at birth and low TCR excision circles that can ultimately recover. Although CD4+ T cell reconstitution in these patients is not completely understood, a lower proportion of naive T cells in adults has suggested a role for homeostatic proliferation. In this study, we present an immunophenotyping study of fraternal twins with low TCR excision circles at birth. Targeted primary immunodeficiency testing revealed a heterozygous variant of uncertain significance in FOXN1 (c.1205del, p.Pro402Leufs*148). We present the immune phenotypes of these two patients, as well as their father who carries the same FOXN1 variant, to demonstrate an evolving immune environment over time. While FOXN1 haploinsufficiency may contribute to thymic defects and T cell lymphopenia, we characterized the transcriptional activity and DNA binding of the heterozygous FOXN1 variant in 293T cells and found the FOXN1 variant to have different effects across several target genes. These data suggest multiple mechanisms for similar FOXN1 variants pathogenicity that may be mutation specific. Increased understanding of how these variants drive transcriptional regulation to impact immune cell populations will guide the potential need for therapeutics, risk for infection or autoimmunity over time, and help inform clinical decisions for other variants that might arise.
摘要：
转录因子FOXN1在胸腺上皮发育中起着确定的作用，以介导成熟胸腺细胞的选择。具有杂合功能丧失FOXN1变体的患者与出生时的T细胞淋巴细胞减少和最终可以恢复的低TCR切除环相关。虽然这些患者的CD4+T细胞重建尚未完全了解，成人中幼稚T细胞的比例较低，这表明其在稳态增殖中起作用。在这项研究中,我们提出了一项出生时具有低TCR切除环的异卵双胞胎的免疫表型研究。有针对性的原发性免疫缺陷检测揭示了FOXN1中具有不确定意义的杂合变体（c.1205del，p.Pro402Leufs*148)。我们介绍了这两名患者的免疫表型，以及他们携带相同FOXN1变体的父亲，证明免疫环境随着时间的推移而不断发展。虽然FOXN1单倍体功能不全可能导致胸腺缺陷和T细胞淋巴细胞减少，我们对293T细胞中杂合FOXN1变体的转录活性和DNA结合进行了表征,发现FOXN1变体在多个靶基因中具有不同的作用.这些数据表明可能是突变特异性的类似FOXN1变体致病性的多种机制。对这些变体如何驱动转录调节以影响免疫细胞群体的理解将指导治疗的潜在需求。随着时间的推移，感染或自身免疫的风险，并帮助告知可能出现的其他变异的临床决策。
