A homozygous STIM1 mutation impairs store-operated calcium entry and natural killer cell effector function without clinical immunodeficiency

The L74P STIM1 change within the EF-hand domain precedes the first Ca2+-binding aspartate residue by 2 amino acids (see Fig E2) and therefore might be expected to distort the Ca2+-binding region of the protein. [...]we compared the response of mutant YFP-STIM1 (L74P) with the depletion of Ca2+ stores after thapsigargin or cyclopiazonic acid (CPA) treatment with that of wild-type YFP-STIM1 and the previously published EF-hand mutant7 YFP-STIM1 (D76A, see Fig E3 in this article's Online Repository at www.jacionline.org). Feature Recessive homozygous mutations Dominant mutations Reference Picard et al, 2009E8 Byun et al, 2010E9 Fuchs et al, 2012E10 Wang et al 2014E11 Schaballie et al, 2015E12 This study Bohm et al, 2013E13 Morin et al, 2014E14 Individual (AR) or diagnosis (AD) Pr1, Pr2, and Pr3[low *] Pr4[dagger] Pr5 and Pr6 Pr7 Pr8 and Pr9 V2 and V3 Tubular aggregate myopathy[double dagger] Stormorken syndrome[double dagger] Predicted protein effect of mutation No protein No protein p.429 R>C p. 146A>V p.165P>Q p.74 L>P All missense in the EF-hand p.304 R>W Age at last examination (y) 1, 5, 6, and 9 2 1.7 and 6 6 8 and 21 11 and 21 Various Various Immune deficiency Life-threatening infections Life-threatening infections Life-threatening infections History of frequent throat infections: no immunologic evaluation performed Life-threatening infections No persistent severe infection NR NR Other immune dysregulation AIHAITP AIHA AIHAITP NR Colitis, psoriasis V3 transient ITP NR NR Skeletal muscle Developmental skeletal myopathy with hypotonia, profound NR Developmental skeletal myopathy with hypotonia, mild NR Developmental skeletal myopathy, profound No abnormalities Clinical myopathy except with 1 mutation Increased CK typical Clinical myopathyIncreased CK Mydriasis Yes NR Yes NR No No NC Yes Sweat glands NC NR Anhidrosis NR Anhidrosis Hypohidrosis NC NC Dental enamel Abnormal NR Abnormal Abnormal Abnormal Abnormal NC NC Died Pr1 died 9 y (during HSCT)Pr2 died 1.5 y (encephalitis) Pr4 died 2 y (Kaposi sarcoma) Pr6 died 1.7 y (sepsis) NR NA NA NA NA Alive Pr3 alive at 6 y (HSCT at 1.3 y) NA Pr5 alive (HSCT) Pr7 lost to follow-up at 5 y Pr8 and Pr9 alive V2 and V3 alive All alive All alive Table E3 Summary of key clinical findings associated with individual reported recessive STIM1 mutations and summarized key clinical findings associated with dominant STIM1 mutations AIHA, Autoimmune hemolytic anemia; AD, autosomal dominant; AR, autosomal recessive; CK, creatine