Dominant mutations in ITPR3 cause Charcot‐Marie‐Tooth disease

Abstract

Objective: ITPR3, encoding inositol 1,4,5-trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot-Marie-Tooth neuropathy. Here, we present genetic and functional evidence that ITPR3 is a Charcot-Marie-Tooth disease gene. Methods: Whole-exome sequencing of four affected individuals in an autosomal dominant family and one individual who was the only affected individual in his family was used to identify diseasecausing variants. Skin fibroblasts from two individuals of the autosomal dominant family were analyzed functionally by western blotting, quantitative reverse transcription PCR, and Ca 2+ imaging. Results: Affected individuals in the autosomal dominant family had onset of symmetrical neuropathy with demyelinating and secondary axonal features at around age 30, showing signs of gradual progression with severe distal leg weakness and hand involvement in the proband at age 64. Exome sequencing identified a heterozygous ITPR3 p.Val615-Met variant segregating with the disease. The individual who was the only affected in his family had disease onset at age 4 with demyelinating neuropathy. His condition was progressive, leading to severe muscle atrophy below knees and atrophy of proximal leg and hand muscles by age 16. Trio exome sequencing identified a de novo ITPR3 variant p.Arg2524Cys. Altered Ca 2+-transients in p.Val615Met patient fibroblasts suggested that the variant has a dominant-negative effect on inositol 1,4,5-trisphosphate receptor type 3 function. Interpretation: Together with two previously identified variants, our report adds further evidence that ITPR3 is a disease-causing gene for CMT and indicates altered Ca 2+ homeostasis in disease pathogenesis.

Disrupted Ca2+ homeostasis and immunodeficiency in patients with functional IP3 receptor subtype 3 defects

“…In contrast, primary ER Ca 2+ release through IP 3 R channels, although associated with several nonimmunological disorders [26,27], has yet to be linked to primary immunodeficiencies. ITPR1, ITPR2 and ITPR3 variants have been suggested to cause (spino-)cerebellar ataxia [28,29], anhidrosis [30], and Charcot-Marie-Tooth disease [31], respectively. In mice, lymphocyte defects were not observed when individual genes were knocked out; in contrast, they were observed only in tripleknockout mice [32][33][34].…”

Novel de novo POLR3B mutations responsible for demyelinating Charcot–Marie–Tooth disease in Japan

“…The common causative genes of CMT1 are PMP22 (CMT1A, 1E), MPZ (CMT1B), LITAF (CMT1C), EGR2 (CMT1D), NEFL (CMT1F), and PMP2 (CMT1G) (https://www.omim.org). Other genes such as FBRN5 , C1orf94 , and ITPR3 have also been found to cause CMT1 3–5 …”

Disrupted Ca2+ homeostasis and immunodeficiency in patients with functional Inositol 1,4,5-trisphosphate receptor subtype 3 defects

“…Three distinct variants were identified across the two compound heterozygous patients. P1 harbors a de novo variant, not reported in any public database but recently suggested as a candidate for causing Charcot-Marie-Tooth syndrome 12 (c.7570C>T:p.Arg2524Cys). Additionally, P1 inherited a c.5549G>A:p.Arg1850Gln substitution from one of his parents that is also present in P2 and one of his parents (referred to as RQ +/- )and reported with an allelic frequency of 6%.…”

“…However, this allele was also observed with dominant inheritance for Charcot-Marie-Tooth in Rönkkö et al . 12 . The absence of a reported immunological phenotype in the previously described patient suggests that sole inheritance of R2524C creates sufficient impairment to lead to Charcot-Marie-Tooth, while preserving sufficient function for normal lymphocyte activation unless coupled with an additional defective allele, as in P1.…”

“…By contrast, the primary ER Ca 2+ release through IP 3 R channels, although associated with several non-immunological disorders 7,8 , has yet to be linked to primary immunodeficiencies. Variants in ITPR1, ITPR2 and ITPR3 have been reported to cause (spino-)cerebellar ataxia 9,10 , anhidrosis 11 , and Charcot-Marie-Tooth disease 12 , respectively. In mice, lymphocyte defects are not observed in individual knockouts, only arising in triple-knockout mice 13–15 .…”