MSH2 – Constitutional Mismatch Repair Deficiency Syndrome

Constitutional mismatch repair deficiency syndrome (CMMRD), also known as mismatch repair cancer syndrome 1, is caused by autosomal recessive inactivation of MSH2 (Gene Symbol). Biallelic MSH2 variants disrupt post-replication DNA repair, leading to early-onset malignancies of the hematopoietic, intestinal, and central nervous systems.

Genetic evidence includes 19 unrelated probands with biallelic MSH2 variants ([PMID:23119205]; [PMID:25400351]; [PMID:25850602]; [PMID:27816604]; [PMID:36715327]; [PMID:17389002]; [PMID:26544533]). Segregation in seven families confirms recessive inheritance ([PMID:26544533]). The variant spectrum is dominated by loss-of-function changes: 11 frameshift, 5 nonsense, and 3 splice site alleles. A recurrent founder frameshift, c.347_350del (p.Asp116fs), has been documented in Turcot families ([PMID:17389002]). Hypomorphic missense changes such as c.188T>A (p.Val63Glu) exhibit reduced mismatch binding in vitro ([PMID:36715327]).

Functional studies in Msh2-null mice demonstrate elevated spontaneous mutation rates and impaired apoptosis after alkylation damage, mirroring the human phenotype ([PMID:10097137]). In vitro, MSH2–MSH6 complexes harboring patient variants show defective mismatch recognition and ATP-dependent dissociation ([PMID:10523644]). Together, these data confirm loss of canonical mismatch repair as the key pathogenic mechanism. No credible refuting evidence has been reported.

Integration of genetic and experimental findings establishes a Strong ClinGen gene–disease association. Early molecular diagnosis of biallelic MSH2 mutations facilitates surveillance and family counseling. Key take-home: AR loss of MSH2 function drives CMMRD, underscoring the need for prompt microsatellite instability testing in pediatric cancers.

References

• Case reports in oncological medicine • 2012 • Turcot syndrome: a synchronous clinical presentation of glioblastoma multiforme and adenocarcinoma of the colon. PMID:23119205
• Indian journal of human genetics • 2014 • Constitutional mismatch repair deficiency syndrome: Do we know it? PMID:25400351
• Neurosurgery • 2015 • An Unusual Case of Constitutional Mismatch Repair Deficiency Syndrome With Anaplastic Ganglioglioma, Colonic Adenocarcinoma, Osteosarcoma, Acute Myeloid Leukemia, and Signs of Neurofibromatosis Type 1: Case Report. PMID:25850602
• Urology • 2017 • Invasive High-grade Upper Tract Urothelial Carcinoma in a 14-Year-Old Girl. PMID:27816604
• Nucleic Acids Research • 2023 • Unexpected moves: a conformational change in MutSα enables high-affinity DNA mismatch binding. PMID:36715327
• European journal of neurology • 2007 • Turcot syndrome confirmed with molecular analysis. PMID:17389002
• Pediatric blood & cancer • 2016 • Constitutional Mismatch Repair Deficiency in Israel: High Proportion of Founder Mutations in MMR Genes and Consanguinity. PMID:26544533
• Proceedings of the National Academy of Sciences of the United States of America • 1999 • Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine. PMID:10097137
• Molecular and Cellular Biology • 1999 • Separation-of-function mutations in Saccharomyces cerevisiae MSH2 that confer mismatch repair defects but do not affect nonhomologous-tail removal during recombination. PMID:10523644

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