MSX1 – Tooth Agenesis

MSX1 encodes a homeodomain transcription factor essential for early odontogenic mesenchyme–epithelium interactions and craniofacial development. Heterozygous LOF variants in MSX1 cause autosomal dominant non-syndromic tooth agenesis, ranging from hypodontia to oligodontia, often with selective absence of second premolars and third molars.

Multiple unrelated families harbor truncating MSX1 variants that co-segregate with tooth agenesis under an AD model. A novel nonsense variant c.610G>T (p.Glu204Ter) was identified in a child and all mutation-positive relatives affected by oligodontia (PMID:30192788). Similarly, a heterozygous c.565C>T variant was found in affected members of a Chinese family with cleft lip and tooth agenesis (PMID:22813217). Frameshifts such as c.128_147del (p.Met43SerfsTer125) exhibit full penetrance in familial oligodontia and disrupt MSX1 nuclear localization (PMID:30134957).

Functional assays in vitro and in vivo support a haploinsufficiency mechanism. The R31P homeodomain missense mutant shows severely reduced DNA binding, no dominant-negative activity, and fails to repress target promoters in limb ectopic expression (PMID:9742121). Mouse Msx1 knockouts and rescue experiments further confirm that reduced Msx1 dosage impairs tooth development.

MSX1 interacts with PAX9 and BMP pathway components to regulate Bmp4 expression in dental mesenchyme, coordinating the bud-to-cap transition. Disruption of MSX1–PAX9 cooperativity arrests odontogenesis; missense variants in the homeodomain abrogate this synergy, abolishing Bmp4 promoter activation and dental cusp formation (PMID:8696335).

Rare non-coding and common polymorphisms (e.g., c.*6C>T) show variable association, indicating oligogenic modifiers and regulatory element involvement. Negative mutation screens in some cohorts highlight genetic heterogeneity and potential epigenetic modulation.

Collectively, definitive genetic and moderate functional evidence establish MSX1 haploinsufficiency as a cause of AD tooth agenesis. MSX1 testing is clinically indicated in patients with familial hypodontia/oligodontia to inform diagnosis, genetic counseling, and early intervention.

References

• Molecular and Cellular Biology • 1998 • Haploinsufficiency of MSX1: a mechanism for selective tooth agenesis. PMID:9742121
• Archives of oral biology • 2012 • Novel nonsense mutation in MSX1 causes tooth agenesis with cleft lip in a Chinese family. PMID:22813217
• PLoS One • 2018 • Next generation sequencing reveals a novel nonsense mutation in MSX1 gene related to oligodontia. PMID:30192788
• Stem Cell Research & Therapy • 2018 • A novel mutation of MSX1 in oligodontia inhibits odontogenesis of dental pulp stem cells via the ERK pathway. PMID:30134957
• Nature Genetics • 1996 • A human MSX1 homeodomain missense mutation causes selective tooth agenesis. PMID:8696335

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