# Fine mapping of heterozygous IL6ST nonsense variants underlying autosomal dominant hyper-IgE syndrome

## TL;DR

This study identifies new genetic variants in the IL6ST gene that cause a rare immune disorder called hyper-IgE syndrome by disrupting normal protein function.

## Contribution

The paper reports two novel IL6ST nonsense variants and shows how their location determines disease causality and dominant negative effects.

## Key findings

- Premature stop codons downstream of F641 in IL6ST lead to loss-of-function and dominant negative effects.
- GP130 accumulation on the cell surface is a diagnostic marker for HIES caused by heterozygous IL6ST variants.
- The recycling motif is essential for preventing mutant GP130 accumulation and dominant negative activity.

## Abstract

Loss-of-function (LOF) variants in IL6ST, encoding GP130, can cause hyper-IgE syndrome (HIES). Monoallelic LOF variants in IL6ST lead to HIES when located in the intracellular domain downstream of box 1/2 and upstream of the STAT3 phosphorylation sites and the recycling motif, due to their dominant negative (DN) activity. In this region, 2 previously unreported IL6ST variants, p.K702Sfs7* and p.Y759Wfs26*, were identified in 2 families with autosomal dominant (AD) HIES. Both variants were LOF and exhibited DN effects, leading to the accumulation of mutant GP130 on the cell surface. The p.K702Sfs7* mutation was the most upstream N-terminal mutation linked to HIES caused by heterozygous IL6ST variants. Comprehensive screening of IL6ST mutants revealed that most premature terminations downstream of amino acid F641, at the end of the transmembrane domain, resulted in LOF and DN effects via GP130 accumulation on the cell surface. The absence of the recycling motif (positions 782–787) in surface-expressed LOF GP130 led to its accumulation, contributing to the DN effect. The importance of intracellular truncating IL6ST variants can possibly be predicted based on the location of the premature stop codon. GP130 accumulation on the cell surface is a characteristic and potentially diagnostic finding in patients with HIES with heterozygous IL6ST variants.

The inheritance patterns of IL6ST variants may depend on the stop codon position, with GP130 accumulation serving as a diagnostic marker for autosomal inheritance.