Citations 2
NK cell defects in X-linked pigmentary reticulate disorder
Starokadomskyy, Petro , Wilton, Katelynn M. , Krzewski, Konrad , Lopez, Adam M., Sifuentes-Dominguez, Luis , Overlee, Brittany L., Ray, Ann , Gil‐Krzewska, Aleksandra, Peterson, Mary , Rohena, Luis , Grunebaum, Eyal , Grishin, Nick V. , Billadeau, Daniel D. , Chen, Qing , Kinch, Lisa N. , Zinn, Andrew R. , Burstein, Ezra
JCI Insight | October 31, 2019 | Volume: 4 | Issue: 21 | Pages: No page available
X-linked reticulate pigmentary disorder (XLPDR, Mendelian Inheritance in Man #301220) is a rare syndrome characterized by recurrent infections and sterile multiorgan inflammation. The syndrome is caused by an intronic mutation in POLA1, the gene encoding the catalytic subunit of DNA polymerase-α (Pol-α), which is responsible for Okazaki fragment synthesis during DNA replication. Reduced POLA1 expression in this condition triggers spontaneous type I interferon expression, which can be linked to the autoinflammatory manifestations of the disease. However, the history of recurrent infections in this syndrome is as yet unexplained. Here we report that patients with XLPDR have reduced NK cell cytotoxic activity and decreased numbers of NK cells, particularly differentiated, stage V, cells (CD3 – CD56 dim ). This phenotype is reminiscent of hypomorphic mutations in MCM4 , which encodes a component of the minichromosome maintenance (MCM) helicase complex that is functionally linked to Pol-α during the DNA replication process. We find that POLA1 deficiency leads to MCM4 depletion and that both can impair NK cell natural cytotoxicity and show that this is due to a defect in lytic granule polarization. Altogether, our study provides mechanistic connections between Pol-α and the MCM complex and demonstrates their relevance in NK cell function.
Ebstein anomaly, left ventricular non‐compaction, and early onset heart failure associated with a de novo α‐tropomyosin gene mutation
Kelle, Angela M. , Bentley, S , Rohena, Luis , Olson, Timothy M. , Cabalka, Allison K. , Olson, Timothy M
American Journal of Medical Genetics Part A | May 13, 2016 | Volume: 170 | Issue: 8 | Pages: 2186-2190
Ebstein anomaly of the tricuspid valve (EA) can be associated with left ventricular non‐compaction (LVNC), a rare congenital cardiomyopathy. We report a 2 year‐old female with EA and severe tricuspid regurgitation, LVNC, pulmonary hypertension, and chronic biventricular systolic heart failure, who died during evaluation for cardiac transplantation. Gene panel testing revealed a heterozygous de novo missense mutation in TPM1, which encodes the cardiac sarcomeric thin filament protein α‐tropomyosin. The c.475G>A variant results in a p.Asp159Asn substitution, altering a highly conserved residue predicted to be damaging to protein structure and function. TPM1 is the second gene linked to EA with LVNC in humans, implicating overlap in the molecular basis of structural and myopathic heart disease. © 2016 Wiley Periodicals, Inc.