A novel bi-allelic loss-of-function mutation in STIM1 expands the phenotype of STIM1-related diseases

Alexandra Salvi (1) , Skrypnyk Cristina (2) , Nathalie da Silva (1) , Jon Andoni Urtizberea (3) , Bakhiet Moiz (2) , Catherine Robert (1) , Nicolas Levy (1) , André Mégarbané (4) , Valérie Delague (1) , Marc Bartoli (1)

1 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
2 Arabian Gulf University
3 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
4 Institut Jérôme Lejeune

STIM1, the stromal interaction molecule 1, is the key protein for maintaining calcium concentration in the endoplasmic reticulum by triggering the Store Operated Calcium Entry (SOCE). Bi-allelic mutations in STIM1 gene are responsible for a loss-offunction in patients affected with a CRAC channelopathy syndrome in which severe combined immunodeficiency syndrome (SCID-like), autoimmunity, ectodermal dysplasia and muscle hypotonia are combined. Here, we studied two siblings from a consanguineous Syrian family, presenting with muscle weakness, hyperlaxity, elastic skin, tooth abnormalities, dysmorphic facies, hypoplastic patellae and history of respiratory infections. Using exome sequencing, we have identified a new homozygous frameshift mutation in STIM1: c.685delT [p.(Phe229Leufs*12)], leading to a complete loss of STIM1 protein. In this study, we describe an unusual phenotype linked to STIM1 mutations, combining clinical signs usually observed in different STIM1-related diseases. In particular, we confirmed that the complete loss of STIM1 function is not always associated with severe immune disorders. Altogether, our results broaden the spectrum of phenotypes associated with mutations in STIM1 and opens new perspectives on the pathological mechanisms associated with a defect in the proteins constituting the SOCE complex.

Mots clés: SOCE; Muscles; STIM1; CRAC

Domaines: Sciences du Vivant [q-bio]; Génétique humaine

Alexandra Salvi, Skrypnyk Cristina, Nathalie da Silva, Jon Andoni Urtizberea, Bakhiet Moiz, et al.. A novel bi-allelic loss-of-function mutation in STIM1 expands the phenotype of STIM1-related diseases. Clinical Genetics, In press. ⟨hal-03184458v2⟩