TRPS1 – Trichorhinophalangeal Syndrome Type III

Trichorhinophalangeal syndrome type III (TRP III) is caused by heterozygous mutations in the TRPS1 zinc-finger transcription factor gene, presenting with severe brachydactyly in addition to sparse hair, a pear-shaped nose, short stature and cone-shaped epiphyses. A single sporadic European patient refined the TRP III spectrum, with neither parent affected, indicating a de novo event in one proband ([PMID:10405449]). Recent molecular genetic analysis identified the in-frame deletion c.880_882del (p.Lys294del) in TRPS1 in a Chinese family with TRP I, supporting pathogenicity of similar loss-of-function alleles ([PMID:36990068]).

The disorder follows an autosomal dominant inheritance pattern with complete penetrance and no evidence of parental mosaicism or transmission in the index family ([PMID:10405449]).

Clinical features include sparse hair (HP:0008070), pear-shaped nose (HP:0000447), short stature (HP:0004322) and cone-shaped epiphyses of the middle phalanges (HP:0010259) in all reported TRP III patients ([PMID:10405449]).

Functional studies demonstrate that TRPS1 nuclear localization depends on the RRRTRKR motif (NLS2), with p.Arg965His and p.Arg965Cys mutations abolishing nuclear import in vitro ([PMID:14560312]). SUMOylation at Lys1192 and Lys1201 is critical for transcriptional repression, as mutation of these sites abrogates TRPS1 repressive activity ([PMID:17391059]). Mouse Trps1 haploinsufficiency models recapitulate chondrodysplasia and craniofacial abnormalities, and genetic interaction with Runx2 underscores a haploinsufficiency mechanism ([PMID:17997399]; [PMID:18424451]). In palatal fusion assays, Trps1-null mice exhibit failure of shelf fusion and decreased epithelial expression of TGF-β3 and Twist1 ([PMID:31130868]).

Together, these data support a haploinsufficiency mechanism, whereby loss of TRPS1 transcriptional repression leads to endochondral ossification defects, craniofacial anomalies and brachydactyly. Additional large pedigrees and segregation studies are needed to elevate evidence beyond the limited category. Key take-home: TRPS1 testing enables diagnosis of autosomal dominant TRP III and informs prognostic genetic counseling.

References

• American journal of medical genetics • 1999 • Sporadic case of trichorhinophalangeal syndrome type III in a European patient. PMID:10405449
• Hormone research in paediatrics • 2024 • Molecular Genetic Analysis and Growth Hormone Treatment in a Three-Generation Chinese Family with Tricho-Rhino-Phalangeal Syndrome I. PMID:36990068
• European journal of human genetics : EJHG • 2004 • Novel missense mutations in the TRPS1 transcription factor define the nuclear localization signal. PMID:14560312
• Biological chemistry • 2007 • SUMOylation modulates transcriptional repression by TRPS1. PMID:17391059
• Developmental biology • 2007 • Trps1 regulates proliferation and apoptosis of chondrocytes through Stat3 signaling. PMID:17997399
• Human molecular genetics • 2008 • Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome. PMID:18424451
• Frontiers in physiology • 2019 • Trps1 Regulates Development of Craniofacial Skeleton and Is Required for the Initiation of Palatal Shelves Fusion. PMID:31130868

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