Bi-allelic MCM10 mutations cause telomere shortening with immune dysfunction and cardiomyopathy

Citations Over Time

Abstract

ABSTRACT Minichromosome maintenance protein 10 (Mcm10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 mutations in patients with distinctive but overlapping clinical phenotypes – natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of Mcm10-associated disease, we modeled these mutations in human cell lines. Mcm10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of Mcm10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in Mcm10-deficient cells require endonucleolytic processing by Mus81, as MCM10 : MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic mutations in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes in both NKD and CM patients.

Related Papers

• → Subsenescent Telomere Lengths in Fibroblasts Immortalized by Limiting Amounts of Telomerase(2000)269 cited
• → Telomere Length Dynamics in Telomerase-Positive Immortal Human Cell Populations(1998)105 cited
• Immortalized cells with no detectable telomerase activity. A review.(1997)
• → Effects of reconstitution of telomerase activity on telomere maintenance by the alternative lengthening of telomeres (ALT) pathway(2001)90 cited
• [Relationship between telomere length and clinical and biological characteristics of the cancers with telomerase reactivation].(1998)