Case Report: Novel STIM1 Gain-of-Function Mutation in a Patient With TAM/STRMK and Immunological Involvement

Abstract

Gain-of-function (GOF) mutations in STIM1 are responsible for tubular aggregate myopathy and Stormorken syndrome (TAM/STRMK), a clinically overlapping multisystemic disease characterised by muscle weakness, miosis, thrombocytopaenia, hyposplenism, ichthyosis, dyslexia, and short stature. Several mutations have been reported as responsible for the disease. Herein, we describe a patient with TAM/STRMK due to a novel L303P STIM1 mutation, who not only presented clinical manifestations characteristic of TAM/STRMK but also manifested immunological involvement with respiratory infections since childhood, with chronic cough and chronic bronchiectasis. Despite the seemingly normal main immunological parameters, immune cells revealed GOF in calcium signalling compared with healthy donors. The calcium flux dysregulation in the immune cells could be responsible for our patient’s immune involvement. The patient’s mother carried the mutation but did not exhibit TAM/STRMK, manifesting an incomplete penetrance of the mutation. More cases and evidence are necessary to clarify the dual role of STIM1 in immune system dysregulation and myopathy.

Activation mechanisms and structural dynamics of STIM proteins

“…H72Q, N80T, G81D/N, D84E/G, S88G, L92V, L96V, Y98C, L303P, J Physiol 602.8 K104N, F108I/L, H109N/R/Y, I115F), the majority of which were identified only in single families (Fig. 4A) (Bohm et al, 2013(Bohm et al, , 2014Claeys et al, 2020;Conte et al, 2021;de la Fuente-Munoz et al, 2022;Harris et al, 2017;Noury et al, 2017;Riva et al, 2022;Walter et al, 2015). A recent study also identified a variation within the SAM domain, V138I, which leads to an increase in STIM1 activity, whereas another disease-relevant mutation within the same domain, P165Q, has an opposite effect on protein function (Lacruz & Feske, 2015;Ticci et al, 2021).…”

“…Farther downstream in the C-terminus, substitutions like L303P, R304Q/W/G, K365N, S630F and R749H alter STIM1 function in a clinically relevant manner, as do the LoF alterations R426C and R429C, among others (Fig. 4B) (Bohm & Laporte, 2018;de la Fuente-Munoz et al, 2022;Harris et al, 2017;Morin et al, 2014;Riva et al, 2022). In the following sections, some mechanistic insights on mutation-based alterations in protein function will be reviewed.…”