Neurological Phenotypes of SOCS1 Haploinsufficiency: Insights from Functional and Histological Investigations

TL;DR

This study identifies neurological symptoms like multiple sclerosis and autoimmune encephalitis in a family with a SOCS1 gene variant, expanding the known effects of this genetic condition.

Contribution

The paper reports neurological manifestations as novel features of SOCS1 haploinsufficiency, previously unobserved in this condition.

Findings

A heterozygous SOCS1 variant was linked to neurological symptoms such as multiple sclerosis and autoimmune encephalitis.

Cells with the SOCS1 variant showed increased STAT1 activity and elevated T-cell proliferation in response to cytokines.

Skin biopsy revealed reduced intraepidermal nerve fiber density, indicating peripheral nervous system involvement.

Abstract

Suppressor of cytokine signaling 1 (SOCS1) haploinsufficiency is a recently described inborn error of immunity characterized by autoimmunity, inflammation, lymphoproliferation, and increased infection susceptibility. SOCS1, a negative regulator of cytokine signaling via the JAK/STAT pathway, explains the condition’s broad phenotypic variability. Single nucleotide polymorphisms in SOCS1 have been linked to multiple sclerosis (MS), and SOCS1 mimetics have shown efficacy in MS animal models. However, neurological involvement has not been previously reported in patients with SOCS1 insufficiency. We describe a family with a heterozygous SOCS1 variant, highlighting neurological manifestations such as MS, autoimmune encephalitis, and recurrent complex regional pain syndrome as novel features. Next-Generation Sequencing and segregation analysis were performed on PBMCs from patients and healthy donors. Functional studies included luciferase reporter assays in HeLa cells expressing the SOCS1 mutant, flow cytometry for phenotypic analysis, and gene expression profiling of the type-I interferon (IFN) signature. Intraepidermal nerve fiber density was evaluated via immunohistochemistry on skin biopsy. Genetic analysis confirmed the variant’s inheritance. Transfected cells carrying the SOCS1 variant showed increased STAT1 transcriptional activity after IFN-γ stimulation. Elevated STAT5 phosphorylation and T-cell proliferation were observed in response to IL-2. Peripheral blood revealed an elevated IFN signature during relapse. Skin biopsy showed reduced intraepidermal nerve fiber density. This report expands the clinical spectrum of SOCS1-related disorders to include neurological symptoms, emphasizing SOCS1’s critical role in regulating inflammation in the central and peripheral nervous systems.

The online version contains supplementary material available at 10.1007/s10875-025-01958-z.

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