A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy

Abstract

In eukaryotic cells, phosphoinositides are lipid second messengers important for many cellular processes and have been found dysregulated in several human diseases. X-linked myotubular (centronuclear) myopathy is a severe congenital myopathy caused by mutations in a phosphatidylinositol 3-phosphate (PtdIns3P) phosphatase called myotubularin, and mutations in dominant centronuclear myopathy (CNM) cases were identified in the dynamin 2 gene. The genes mutated in autosomal recessive cases of CNMs have not been found. We have identified a novel phosphoinositide phosphatase (hJUMPY) conserved through evolution, which dephosphorylates the same substrates as myotubularin, PtdIns3P and PtdIns(3,5)P(2), in vitro and ex vivo. We found, in sporadic cases of CNMs, two missense variants that affect the enzymatic function. One of these appeared de novo in a patient also carrying a de novo mutation in the dynamin 2 gene. The other missense (R336Q) found in another patient changes the catalytic arginine residue of the core phosphatase signature present in protein tyrosine/dual-specificity phosphatases and in phosphoinositide phosphatases and drastically reduces the enzymatic activity both in vitro and in transfected cells. The inheritance of the phenotype with regard to this variant is still unclear and could be either recessive with an undetected second allele or digenic. We propose that impairment of hJUMPY function is implicated in some cases of autosomal CNM and that hJUMPY cooperates with myotubularin to regulate the level of phosphoinositides in skeletal muscle.

Clinical utility gene card for: Centronuclear and myotubular myopathies

“…5 Neonatal severe cases should be first tested for all exons of MTM1 and DNM2 exons 8 and 16. In female neonates, MTM1 mutation is associated with skewed X-inactivation or, less frequently, other X--chromosomal abnormalities.…”

“…For MTMR14, incomplete penetrance or mutations acting as modifier alleles have been suggested. 5 In addition, specific DNM2 mutations are found in patients with Charcot-Marie-Tooth neuropathy who do not develop centronuclear myopathies (CMTDIB and CMT2M 23 ).…”

“…5 The most common mutation identified is c.1261-10A4G, which has been demonstrated to affect normal splicing, and occurs in B7% of patients. Large deletions that affect one or more exons occur in B7% of patients.…”

“…14 DNM2: Thirteen heterozygous missense changes or in-frame deletions or insertions have been reported with hotspots at position 368, 369, 465, 522, 618 and 619. 5,[15][16][17][18][19][20] In the middle domain, the recurrent p.R465W mutation is most common, likely accounting for B25% of families, whereas p.E368K and p.R369W are found in B20% and B10% of families, respectively. The PH domain mutation p.R522H is found in roughly 10% of families, whereas mutations of residues 618 and 619 account for about 15% of families.…”

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

“…Third, mutations in protein phosphatases or kinases may account for some rare as yet molecularly uncharacterized muscular dystrophies. For example, mutations in the phosphatase myotubularin 1 are known to cause X‐linked myotubular myopathy56 and a mutation in the phosphatase myotubularin‐releated protein 14 has been shown to cause centronuclear myopathy 57. Fourth, declines in expression of phosphatases or kinases with age may contribute to the onset and/or progression of sarcopenia.…”