TNNT3 – Sheldon-Hall Syndrome

Sheldon-Hall syndrome (SHS; MONDO:0011128) is an autosomal dominant distal arthrogryposis characterized by congenital contractures of distal joints and mild facial involvement. TNNT3 (HGNC:11950) encodes the fast skeletal muscle troponin T subunit, a key regulator of calcium-mediated muscle contraction. Pathogenic variants in TNNT3 disrupt thin filament function, leading to the characteristic limb contractures and occasional vertical talus deformities seen in SHS.

In a multi-center cohort of 105 DA2B probands, pathogenic variants in TNNT3 and three other contractile-apparatus genes accounted for 40% of cases, with TNNT3 variants detected in multiple unrelated families ([PMID:23401156]). A recurrent hotspot mutation, c.187C>T (p.Arg63Cys), was identified by linkage analysis and PCR sequencing in a three-generation Chinese pedigree with SHS and vertical talus, segregating in 3 affected individuals ([PMID:21402185]). The same variant was observed in a second family with variable severity across 3 members (proband, mother, sister) confirming dominant inheritance and segregation in 2 additional relatives ([PMID:36968005]).

All reported TNNT3 variants in SHS are heterozygous missense changes affecting conserved residues within the tropomyosin-binding or troponin-I interaction domains. The recurrent c.187C>T (p.Arg63Cys) variant is found in multiple ethnic backgrounds and has not been reported in population databases, suggesting a founder or recurrent mutational hotspot.

Functional assays demonstrate that the p.Arg63Cys substitution significantly increases TNNT3 protein stability (half-life extended from 2.5 to 7 h) and promotes nuclear accumulation, implicating a toxic gain-of-function mechanism ([PMID:34766372]). In vitro cross-linking of a recombinant Ser155Cys mutant identified the region around residue 155 as critical for troponin C and I interactions, highlighting key structural determinants of thin filament regulation ([PMID:9724539]).

The convergence of genetic segregation in multiple families, identification of recurrent missense variants, and concordant functional data support a strong gene–disease association between TNNT3 and SHS. TNNT3 genetic testing should be included in diagnostic panels for distal arthrogryposis, and functional assays of novel variants may aid in pathogenicity assessment.

Key Take-home: Heterozygous TNNT3 missense variants, particularly c.187C>T (p.Arg63Cys), cause autosomal dominant Sheldon-Hall syndrome through altered troponin T stability and thin filament dysregulation, supporting TNNT3 as a high-priority diagnostic gene.

References

• American journal of medical genetics. Part A • 2013 • Spectrum of mutations that cause distal arthrogryposis types 1 and 2B. PMID:23401156
• European journal of medical genetics • 2011 • A novel mutation in TNNT3 associated with Sheldon-Hall syndrome in a Chinese family with vertical talus. PMID:21402185
• Frontiers in genetics • 2022 • Diagnostic work-up and phenotypic characteristics of a family with variable severity of distal arthrogryposis type 2B (Sheldon-Hall syndrome) and TNNT3 pathogenic variant. PMID:36968005
• Journal of clinical laboratory analysis • 2021 • The distal arthrogryposis-linked p.R63C variant promotes the stability and nuclear accumulation of TNNT3. PMID:34766372
• Biochemistry • 1998 • A recombinant monocysteine mutant (Ser to Cys-155) of fast skeletal troponin T: identification by cross-linking of a domain involved in a physiologically relevant interaction with troponins C and I. PMID:9724539

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