Stormorken Syndrome Caused by a p.R304W STIM1 Mutation: The First Italian Patient and a Review of the Literature

Abstract

Stormorken syndrome is a rare autosomal dominant disease that is characterized by a complex phenotype that includes tubular aggregate myopathy (TAM), bleeding diathesis, hyposplenism, mild hypocalcemia and additional features, such as miosis and a mild intellectual disability (dyslexia). Stormorken syndrome is caused by autosomal dominant mutations in the STIM1 gene, which encodes an endoplasmic reticulum Ca2+ sensor. Here, we describe the clinical and molecular aspects of a 21-year-old Italian female with Stormorken syndrome. The STIM1 gene sequence identified a c.910C > T transition in a STIM1 allele (p.R304W). The p.R304W mutation is a common mutation that is responsible for Stormorken syndrome and is hypothesized to cause a gain of function action associated with a rise in Ca2+ levels. A review of published STIM1 mutations (n = 50) and reported Stormorken patients (n = 11) indicated a genotype-phenotype correlation with mutations in a coiled coil cytoplasmic domain associated with complete Stormorken syndrome, and other pathological variants outside this region were more often linked to an incomplete phenotype. Our study describes the first Italian patient with Stormorken syndrome, contributes to the genotype/phenotype correlation and highlights the possibility of directly investigating the p.R304W mutation in the presence of a typical phenotype.Highlights - Stormorken syndrome is a rare autosomal dominant disease.- Stormoken syndrome is caused by autosomal dominant mutations in the STIM1 gene.- We present the features of a 21-year-old Italian female with Stormorken syndrome.- Our review of published STIM1 mutations suggests a genotype-phenotype correlation.- The p.R304W mutation should be investigated in the presence of a typical phenotype.

Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation

“…TAM/STRMK mutations in the cytosolic coiled‐coil domains are restricted to a single amino acid. p.R304W (c.910C>T) is the most common STIM1 mutation and has been found in 13 unrelated families of different geographic and ethnic origin (Alonso‐Jiménez et al, ; Borsani et al, ; Harris et al, ; Markello et al, ; Misceo et al, ; Morin et al, ; Nesin et al, ). A separate family was reported with a different mutation of the same arginine residue (c.911G>A; p.R304Q; Harris et al, ).…”

“…The majority of the molecularly diagnosed TAM/STRMK patients carry missense mutations in STIM1 (MIM# 605921; Alonso‐Jiménez et al, ; Böhm et al, ; Borsani et al, ; Harris et al, ; Hedberg et al, ; Markello et al, ; Misceo et al, ; Morin et al, ; Nesin et al, ; Noury et al, ; Walter et al, ), while missense mutations in ORAI1 (MIM# 610277; Böhm et al, ; Endo et al, ; Garibaldi et al, ; Nesin et al, ) are less frequent. Both genes encode key players of store‐operated Ca 2+ entry (SOCE), an essential and ubiquitous mechanism regulating Ca 2+ homeostasis and thereby controlling a multitude of Ca 2+ ‐dependent pathways and cellular functions including muscle contraction (Putney, ).…”

“…STIM1 is composed of a luminal N‐terminal part comprising Ca 2+ sensing EF‐hands, a single transmembrane domain, and a cytosolic C‐terminus with coiled‐coil domains encompassing the STIM1–ORAI1 activating domain (SOAR; Park et al, ; Stathopulos et al, ; Yuan et al, ). To date, 15 different heterozygous STIM1 mutations have been described in TAM/STRMK, including 12 mutations in the luminal EF‐hands (Böhm et al, ; Harris et al, ; Hedberg et al, ; Markello et al, ; Noury et al, ; Walter et al, ), two mutations in the cytosolic coiled‐coil domains, and one mutation in the cytosolic inhibitory domain (ID; Alonso‐Jiménez et al, ; Borsani et al, ; Harris et al, ; Markello et al, ; Misceo et al, ; Morin et al, ; Nesin et al, ; Okuma et al, ). With exception of a frameshift, all are missense mutations affecting highly conserved amino acids.…”

Functional analyses ofSTIM1mutations reveal a common pathomechanism for tubular aggregate myopathy and Stormorken syndrome

“…Tubular aggregate myopathy essentially affects skeletal muscle, and a subset of TAM patients harboring STIM1 EF-hand mutations additionally manifested one or several signs of Stormorken syndrome (3–5, 8, 9, 18). Conversely, Stormorken syndrome patients carrying the most common R304W mutation usually present the full clinical picture of TAM, miosis, thrombocytopenia, hyposplenism, ichthyosis, short stature, and dyslexia (7, 10–14), but individual patients with muscle weakness as the main clinical sign were also reported (9). This illustrates that TAM and Stormorken syndrome form a clinical continuum, and raises the question on the underlying common and diverging pathomechanisms.…”

“…Fourteen different STIM1 mutations have been described in patients with TAM and Stormorken syndrome, including 12 mutations in the luminal EF-hands, and two mutations in the cytosolic CC1 domain (3–14, 18). Patients with EF-hand mutations mainly manifest a muscle phenotype and only isolated multi-systemic features, while the most common R304W substitution in the cytosolic CC1 domain, found in thirteen unrelated families, was essentially described with the full clinical picture of Stormorken syndrome (7, 10–14).…”