# FNIP1 Deficiency: Pathophysiology and Clinical Manifestations of a Rare Syndromic Primary Immunodeficiency

## TL;DR

FNIP1 deficiency causes a rare immune disorder with metabolic and immunological issues, highlighting its role in cellular stress adaptation.

## Contribution

This paper characterizes the clinical and pathophysiological features of human FNIP1 deficiency, revealing its role in immune and metabolic dysregulation.

## Key findings

- FNIP1 deficiency in humans leads to immunological and hematological abnormalities.
- FNIP1 loss disrupts immune cell development and mitochondrial homeostasis in murine models.
- FNIP1 dysfunction is linked to immune dysregulation and metabolic perturbations in affected patients.

## Abstract

Folliculin-interacting protein 1 (FNIP1) is a key regulator of cellular metabolism and immune homeostasis, integrating nutrient signaling with proteostasis. FNIP1 forms a complex with folliculin (FLCN) to regulate the mechanistic target of rapamycin complex 1 (mTORC1), functioning as a GTPase-activating protein (GAP) for RagC/D. Additionally, FNIP1 interacts with heat shock protein 90 (HSP90) and undergoes phosphorylation, glycosylation, and ubiquitination, which dynamically regulate its stability and function. Evidence from murine models suggests that FNIP1 loss disrupts immune cell development and mitochondrial homeostasis. However, FNIP1 deficiency in humans remains incompletely characterized, and its full phenotypic spectrum is likely underestimated. Notably, FNIP1-deficient patients exhibit immunological and hematological abnormalities, immune dysregulation, and metabolic perturbations, emphasizing its role in cellular adaptation to stress. Understanding the mechanistic basis of FNIP1 dysfunction in human tissues will be critical for delineating its contributions to immune and metabolic disorders and identifying targeted interventions.