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