Tricho-rhino-phalangeal Syndromes Research Articles

Novel deletion mutation of TRPS1 gene in a Chinese patient of trichorhinophalangeal syndrome type I

Tricho–rhino–phalangeal syndrome (TRPS) is a rare autosomal dominant disorder. Deletion or mutation of the TRPS1 gene leads to the tricho–rhino–phalangeal syndromes type I or type III. In this article, we describe a Chinese patient affected with type I TRPS and showing prominent pilar, rhinal and phalangeal abnormalities. Mutational screening and sequence analysis of TRPS1 gene revealed a previously unidentified four-base-pair deletion of nucleotides 1783–1786 (c.1783_1786delACTT). The mutation causes a frame shift after codon 593, introducing a premature stop codon after 637 residues in the gene sequence. This deletion is an unquestionable loss-of-function mutation, deleting all the functionally important parts of the protein. Our novel discovery indicates that sparse hair and metacarpal defects of tricho–rhino–phalangeal syndromes in this patient are due to this TRPS1 mutation. And this data further supports the critical role of TRPS1 gene in hair and partial skeleton morphogenesis.

Rheumatologic and neurological events in an elderly patient with tricho-rhino-phalangeal syndrome type I

Sparse scalp hair, a peculiar shape of the nose, and cone-shaped epiphyses of the phalanges are the hallmarks of the tricho-rhino-phalangeal syndromes (TRPS). Short stature, hip dysplasia, and malformations of inner organs including mitral valve prolpase have also often been described for these conditions. Here, we described a 64-year-old woman with molecularly proved TRPS I and several atypical late-onset rheumatologic and neurological symptoms.

A novel nonsense mutation in the TRPS1 gene in a case of trichorhinophalangeal syndrome type I

The trichorhinophalangeal syndromes are rare malformation syndromes with autosomal dominant inheritance. Diagnostic features include distinctive facial dysmorphisms and various skeletal abnormalities. The affected gene, the TRPS1 on 8q24.1, was first identified in 2000 and more than 50 mutations have been found. We present a patient with a novel nonsense mutation in the TRPS1 gene.

Mutations in TRPS1 gene in trichorhinophalangeal syndrome type I in Asian patients

The trichorhinophalangeal syndromes (TRPSs) are rare hereditary diseases with mainly autosomal dominant inheritance. Three different forms sharing similar clinical features with heterogeneous mutations have been identified: type I (TRPS I), type II (TRPS II) and type III (TRPS III). These syndromes have characteristic facial abnormalities such as sparse and slow-growing scalp hair, laterally sparse eyebrows, bulbous pear-shaped nose, elongated and flat philtrum, thin upper lip, and protruding ears. Various skeletal abnormalities are also frequently noted: short stature, shortening of the phalanges and metacarpals, cone-shaped epiphyses and Perthes-like change of the hips.(1-4) The TRPS1 gene was first identified in 2000 and mapped to 8q24.1.(1) More than 50 mutations have been found in the gene to date. We here report mutation analysis of eight patients with the typical phenotype of TRPS I, revealing five novel mutations.

Tricho-Rhino-Phalangeal Syndrome with Supernumerary Teeth

Tricho-rhino-phalangeal syndromes (TRPS) are caused by mutation or deletion of TRPS1, a gene encoding a GATA transcription factor. These disorders are characterized by abnormalities of the hair, face, and selected bones. Rare cases of individuals with TRPS displaying supernumerary teeth have been reported, but none of these has been examined molecularly. We used two different approaches to investigate a possible role of TRPS1 during tooth development. We looked at the expression of Tprs1 during mouse tooth development and analyzed the craniofacial defects of Trps1 mutant mice. In parallel, we investigated whether a 17-year-old Thai boy with clinical features of TRPS and 5 supernumerary teeth had mutation in TRPS1. We report here that Trps1 is expressed during mouse tooth development, and that an individual with TRPS with supernumerary teeth has the amino acid substitution A919V in the GATA zinc finger of TRPS1. These results suggest a role for TRPS1 in tooth morphogenesis.

Deletion 22q13.3 syndrome

The deletion 22q13.3 syndrome (deletion 22q13 syndrome or Phelan-McDermid syndrome) is a chromosome microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features. The deletion occurs with equal frequency in males and females and has been reported in mosaic and non-mosaic forms. Due to lack of clinical recognition and often insufficient laboratory testing, the syndrome is under-diagnosed and its true incidence remains unknown. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Behavior is autistic-like with decreased perception of pain and habitual chewing or mouthing. The loss of 22q13.3 can result from simple deletion, translocation, ring chromosome formation and less common structural changes affecting the long arm of chromosome 22, specifically the region containing the SHANK3 gene. The diagnosis of deletion 22q13 syndrome should be considered in all cases of hypotonia of unknown etiology and in individuals with absent speech. Although the deletion can sometimes be detected by high resolution chromosome analysis, fluorescence in situ hybridization (FISH) or array comparative genomic hybridization (CGH) is recommended for confirmation. Differential diagnosis includes syndromes associated with hypotonia, developmental delay, speech delay and/or autistic-like affect (Prader-Willi, Angelman, Williams, Smith-Magenis, Fragile X, Sotos, FG, trichorhinophalangeal and velocardiofacial syndromes, autism spectrum disorders, cerebral palsy). Genetic counseling is recommended and parental laboratory studies should be considered to identify cryptic rearrangements and detect parental mosaicism. Prenatal diagnosis should be offered for future pregnancies in those families with inherited rearrangements. Individuals with deletion 22q13 should have routine examinations by the primary care physician as well as genetic evaluations with referral to specialists if neurological, gastrointestinal, renal, or other systemic problems are suspected. Affected individuals benefit from early intervention programs, intense occupational and communication therapies, adaptive exercise and sport programs, and other therapies to strengthen their muscles and increase their communication skills. No apparent life-threatening organic abnormalities accompany the diagnosis of deletion 22q13.

Partial growth hormone deficiency and changed bone quality and mass in type I trichorhinophalangeal syndrome

The trichorhinophalangeal syndromes (TRPSs) are syndromes due to haploinsufficiency of genes in the chromosome 8q24.12 region. Type I TRPS is characterized by typical facial features including sparse, brittle and fine hair, bulbous nose, and a long philtrum, as well as skeletal abnormalities. Growth retardation is a feature frequently found in these patients, who commonly are of short stature; however, only one case with growth hormone deficiency has been described in a TRPS patient and that patient had type II TRPS. Skeletal morphological abnormalities have been studied, but investigation of bone metabolism and quality in this kind of patients are not available. In this report we describe two cases of type I TRPS with partial growth hormone deficiency and significant bone mass and quality impairment, which was unresponsive to GH treatment.

SUMOylation modulates transcriptional repression by TRPS1

Mutations or deletions of the TRPS1 gene on human chromosome 8q.24.1 cause the tricho-rhino-phalangeal syndromes (TRPS), which are characterized by craniofacial and skeletal malformations. The gene encodes a transcription factor that functions as a repressor for GATA-mediated transcription. The activity of transcription factors is often controlled by posttranslational modifications. We show here that TRPS1 is SUMOylated at multiple sites, both in vivo and in vitro, through interaction with UBC9. Overexpression of wild-type UBC9 enhances TRPS1-mediated transcriptional repression. In contrast, a SUMOylation-deficient UBC9 mutant, which nevertheless still binds TRPS1, has no effect. Of the five potential TRPS1 SUMO-target sites, which were predicted based on a minimal SUMOylation consensus sequence (MCS), two are located within the C-terminal repression domain (RD) at lysine residues 1192 (termed S4) and 1201 (S5). S5 was identified as the major acceptor site within this region, and a point mutation of S5 strongly decreases TRPS1-RD-mediated transcriptional repression. Additional mutation of S4 results in abrogation of SUMOylation at the TRPS1-RD and almost complete loss of the repressive properties of TRPS1. These results identify SUMOylation at the TRPS1-RD as a major mechanism that regulates the function of TRPS1.

The gene associated with trichorhinophalangeal syndrome in humans is overexpressed in breast cancer

A comprehensive differential gene expression screen on a panel of 54 breast tumors and >200 normal tissue samples using DNA microarrays revealed 15 genes specifically overexpressed in breast cancer. One of the most prevalent genes found was trichorhinophalangeal syndrome type 1 (TRPS-1), a gene previously shown to be associated with three rare autosomal dominant genetic disorders known as the trichorhinophalangeal syndromes. A number of corroborating methodologies, including in situ hybridization, e-Northern analysis using ORF EST (ORESTES) and Unigene EST abundance analysis, immunoblot and immunofluorescence analysis of breast tumor cell lines, and immunohistochemistry, confirmed the microarray findings. Immunohistochemistry analysis found TRPS-1 protein expressed in >90% of early- and late-stage breast cancer, including ductal carcinoma in situ and invasive ductal, lobular, and papillary carcinomas. The TRPS-1 gene is also immunogenic with processed and presented peptides activating T cells found after vaccination of HLA-A2.1 transgenic mouse. Human T cell lines from HLA-A*0201+ female donors exhibiting TRPS-1-specific cytotoxic T lymphocyte activity could also be generated.

Novel missense mutations in the TRPS1 transcription factor define the nuclear localization signal.

Deletion or mutation of the TRPS1 gene leads to the tricho-rhino-phalangeal syndromes (TRPS). The gene encodes a zinc-finger transcription factor, which contains two regions with basic amino acids LRRRRG (NLS1) and RRRTRKR (NLS2) that resemble potential nuclear localization signals (NLSs). Here, we describe the identification of novel TRPS1 mutations in patients with TRPS type I (TRPS I) and provide, by reconstructing the mutant TRPS1 proteins and subcellular localization studies, evidence that only the RRRTRKR motif functions as a NLS. Two different mutations affect the last arginine residue of this motif. The exchanges of arginine to histidine, found in two unrelated patients with TRPS I, as well as the exchange of arginine to cysteine, found in another unrelated patient, prevent the translocation of the mutant TRPS1 to the nucleus when ectopically expressed in COS 7 cells. In contrast, a mutant that lacks the conserved GATA-type zinc-finger domain and most of the LRRRRG motif is able to enter the nucleus.

Transcriptional repression and developmental functions of the atypical vertebrate GATA protein TRPS1.

Known vertebrate GATA proteins contain two zinc fingers and are required in development, whereas invertebrates express a class of essential proteins containing one GATA-type zinc finger. We isolated the gene encoding TRPS1, a vertebrate protein with a single GATA-type zinc finger. TRPS1 is highly conserved between Xenopus and mammals, and the human gene is implicated in dominantly inherited tricho-rhino-phalangeal (TRP) syndromes. TRPS1 is a nuclear protein that binds GATA sequences but fails to transactivate a GATA-dependent reporter. Instead, TRPS1 potently and specifically represses transcriptional activation mediated by other GATA factors. Repression does not occur from competition for DNA binding and depends on a C-terminal region related to repressive domains found in Ikaros proteins. During mouse development, TRPS1 expression is prominent in sites showing pathology in TRP syndromes, which are thought to result from TRPS1 haploinsufficiency. We show instead that truncating mutations identified in patients encode dominant inhibitors of wild-type TRPS1 function, suggesting an alternative mechanism for the disease. TRPS1 is the first example of a GATA protein with intrinsic transcriptional repression activity and possibly a negative regulator of GATA-dependent processes in vertebrate development.

Phalangeal cone-shaped epiphyses of the hand: their natural history, diagnostic sensitivity, and specificity in cartilage hair hypoplasia and the trichorhinophalangeal syndromes I and II.

Phalangeal cone-shaped epiphyses are an ideal object for the radiologist to study with temporal reasoning, to examine their shape, diagnostic usefulness, natural history and effect on pathophysiology. Radiographs of the hands of 60 patients with cartilage hair hypoplasia (CHH), 69 with trichorhinophalangeal syndrome I (TRP I) and 11 with TRP II were examined, including 26 longitudinal observations. The early phases of cone development were recorded. In CHH a characteristic mesophalangeal type of cone in 42/47 patients of the "Age Suitable for Classification" (ASC) was detected. All 46 TRP I and 9 TRP II patients in the ASC had the previously described mesophalangeal cone type 12. However, 1/4 of these TRP I and all TRP II cases presented a milder variant of type 12: type 12 A. A complex sequence of secondary changes in the proximal interphalangeal joints in TRP I leading eventually to subluxation was recorded. It can be concluded that in the ASC the cones described are highly sensitive but not specific diagnostic indicators. In infancy and early childhood, other phalangeal changes were found, which may be of diagnostic help.

The Tricho-rhino-phalangeal syndromes I and II

The Tricho-rhino-phalangeal syndromes I and II