Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants 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 variants 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 variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients.

Purpose: Early exposure and surgical mentorship can augment interest in surgery. We evaluate the effect and feasibility of offering education and mentorship opportunities in surgery to premedical students at our institution through an undergraduate surgery interest group (USIG). Materials and Methods: We conducted a 1-year assessment of our USIG and reviewed its organizational structure, funding resources, media promotion, and educational activities. Our USIG hosted introductory-level surgical skills workshops, guest lectures by surgeons, and various facility tours. To assess participants' interests, as well as the influences on them to pursue a surgical profession, we analyzed pre-and post-event questionnaires. Similar questionnaires were completed by medical students in our medical student surgery interest group to compare any differences in perception between premedical and medical students. Results: Our USIG currently has 378 undergraduate student members, with a higher proportion of women than in our medical student surgery interest group (P < 0.003). Neurosurgery was the most popular career choice among undergraduate participants. Participants reported the highest satisfaction with suturing and high-fidelity trauma surgery skills workshops. Undergraduate participants indicated that their intrinsic interest in the sciences is the highest motivation to pursue a surgical profession. Resident lifestyle and social obligations of a surgical career were actually positive influences for undergraduate participants; in contrast, medical students viewed those variables as negative factors. Conclusion: Our USIG was met with enthusiasm by premedical students and faculty alike. Participation strengthened premedical students' interest in pursuing surgery and increased their understanding of the surgical profession. Early mentorship may positively influence premedical students' perception of surgical careers. USIG is economically feasible and timeefficient; we encourage other academic institutions and educators to consider investing in similar interest groups.

Minichromosome maintenance protein 10 (Mcm10) is essential for eukaryotic DNA replication initiation and fork stability. Recently, a compound heterozygous MCM10 mutation was identified in a patient who presented with natural killer (NK) cell deficiency.To understand the mechanism of disease, we modeled this mutation in human cell lines.We demonstrate that Mcm10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere maintenance defects.Our data suggests that Mcm10 deficiency constrains telomerase-dependent telomere extension. This limitation can be overcome by increasing telomerase activity, although defects in telomere replication persist. We propose that stalled replication forks in Mcm10-deficient cells arrest terminally, especially within hard-to-replicate regions, and require nuclease processing involving Mus81, as MCM10:MUS81 double mutants displayed decreased viability and accelerated telomere erosion. Our results reveal that Mcm10 is critical for telomere replication and provide insights into how MCM10 mutations cause NK cell deficiency.

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