A novel frameshift mutation in the TRPS1 gene caused Tricho-rhino-phalangeal syndrome type I and III in a Japanese family.
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ABSTRACT:
SUBMITTER: Itoh M
PROVIDER: S-EPMC4965513 | biostudies-literature | 2016 Jul
REPOSITORIES: biostudies-literature
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A novel frameshift mutation in the TRPS1 gene caused Tricho-rhino-phalangeal syndrome type I and III in a Japanese family.
Itoh Masatsune M Kittaka Yuko Y Niida Yo Y Saikawa Yutaka Y
Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 20160720 3
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Project description:BackgroundTricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant disorder characterized by craniofacial and skeletal malformations including short stature, thin scalp hair, sparse lateral eyebrows, pear-shaped nose and cone shaped epiphyses. This condition is caused by haploinsufficiency of the TRPS1 gene. Previous genotype-phenotype studies have correlated exon 6 missense mutations with TRPS type III, a severe form of type I with pronounced, facial characteristics, short stature and brachydactyly and differing from type II by the absence of exostoses and mental retardation.Case presentationWe report the first case of a Moroccan family, a father and his three children, in which the diagnosis of type III TRPS was suspected based on severe clinical and radiological features. Molecular analysis of the TRPS1 gene revealed a novel missense mutation in exon 6, (p.Ala932Ser), located in the GATA-type DNA-binding zinc finger domain.ConclusionOur observations in this kindred support the previous genotype-phenotype results suggesting that patients with more pronounced facial characteristics and more severe shortening of hands and feet are more likely to have mutation in exon 6 of TRPS1.
| S-EPMC5415804 | biostudies-literature
Project description:BackgroundTricho-rhino-phalangeal syndrome (TRPS) is a rare autosomal dominant disorder characterized by craniofacial and skeletal malformations including short stature, thin scalp hair, sparse lateral eyebrows, a pear-shaped nose, and cone-shaped epiphyses. This condition is caused by haploinsufficiency or dominant-negative effect of the TRPS1 gene.MethodsIn this study, we analyzed the clinical and genetic data of five unrelated TRPS patients. They were suspected of having TRPS on the basis of clinical and radiological features including typical hair and facial features, as well as varying degrees of skeletal abnormalities. Next-generation sequencing was performed to identify variants of the TRPS1 gene in the five patients.ResultsIn patient 1, we found a novel mutation at c.1338C>A (p.Tyr446*) (de novo). Patient 2 had a novel phenotype of hydrocephaly and Arnold-Chiari syndrome and we also found a maternally inherited novel mutation at c.2657C>A (p.Ser886*). Patient 3 had a de novo novel mutation at c.2726G>C (p.Cys909Ser) leading to more severe phenotypes. Patient 4 had a paternally inherited known mutation at c.2762G>A (p.Arg921Gln). Patient 5 with a novel phenotype of hepatopathy had a novel deletion at [GRCh37] del(8)(q23.3-q24.11) chr8:g.116,420,724-119,124,058 (over 2,700 kb). In addition, the patient 3 who harboring missense variants in the GATA binding domain of TRPS1 showed more severe craniofacial and skeletal phenotypes.ConclusionsWe describe four novel mutations and two novel phenotypes in five patients. The mutational and phenotypic spectrum of TRPS is broadened by our study on TRPS mutations. Our results reveal the significance of molecular analysis of TRPS1 for improving the clinical diagnosis of TRPS.
| S-EPMC7549555 | biostudies-literature
Project description:Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.
| S-EPMC1234936 | biostudies-literature
Project description:Tricho-rhino-phalangeal syndrome (TRPS) is a rare autosomal dominant malformation caused by mutations involving the TRPS1 gene. Patients with TRPS exhibit distinctive craniofacial and skeletal abnormalities. This report presents three intra-familial cases with TRPS1 gene mutations that showed the characteristic features of TRPS. A 13-year-old boy was admitted to Department of Endocrinology for the evaluation of short stature. Physical examination revealed that the boy had thin sparse hair, pear-shaped nose, protruding ears, small jaw and brachydactyly. A survey of his family history indicated that the boy's sister and mother shared the same clinical features. Radiological techniques demonstrated a different degree of skeletal abnormalities in these siblings. Next-generation sequencing and quantitative PCR were performed and showed a novel deletion mutation in exons 3-5 in the three familial cases, confirming the diagnosis of TRPS I. The healthy father did not carry the deletion mutation. Currently, there was no specific therapy for TRPS I; however, genetic consultation may be useful for family planning.
| S-EPMC9716017 | biostudies-literature
Project description: Not available
| S-EPMC6183015 | biostudies-literature
Project description:GATA transcription factors mediate cell differentiation in diverse tissues, and their dysfunction is associated with certain congenital human disorders. The six classical vertebrate GATA proteins, GATA-1 to GATA-6, are highly homologous, bear two tandem zinc fingers of the C(4) (GATA) type, and activate transcription. TRPS1, the only other vertebrate protein with the GATA motif, is a large, multitype zinc finger protein that harbors a single DNA-binding GATA domain and represses transcription. Monoallelic TRPS1 mutations cause two dominantly inherited human developmental disorders of the hair, face, and digits, tricho-rhino-phalangeal syndrome (TRPS) types I (MIM 190350) and III (MIM 190351); missense GATA domain mutations account for the more severe type III form. Here we report that heterozygous mice with deletions of the TRPS1 GATA domain (TRPS1(+/Deltagt)) display facial anomalies that overlap with findings for TRPS, whereas TRPS1(Deltagt/Deltagt) mice additionally reveal a complete absence of vibrissae. Unexpectedly, TRPS1(Deltagt/Deltagt) mice die of neonatal respiratory failure resulting from abnormalities of the thoracic spine and ribs. Heterozygotes also develop thoracic kyphoscoliosis with age and reveal structural deficits in cortical and trabecular bones. These findings directly implicate the GATA type zinc finger of TRPS1 in regulation of bone and hair development and suggest that skeletal abnormalities emphasized in descriptions of TRPS are only the extreme manifestations of a generalized bone dysplasia.
| S-EPMC139891 | biostudies-literature
Project description:Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant craniofacial and skeletal dysplasia that is caused by mutations involving the TRPS1 gene. Patients with TRPS have short stature, hip abnormalities, cone-shaped epiphyses and premature closure of growth plates reflecting defects in endochondral ossification. The TRPS1 gene encodes for the transcription factor TRPS1 that has been demonstrated to repress transcription in vitro. To elucidate the molecular mechanisms underlying skeletal abnormalities in TRPS, we analyzed Trps1 mutant mice (Trps1DeltaGT mice). Analyses of growth plates demonstrated delayed chondrocyte differentiation and accelerated mineralization of perichondrium in Trps1 mutant mice. These abnormalities were accompanied by increased Runx2 and Ihh expression and increased Indian hedgehog signaling. We demonstrated that Trps1 physically interacts with Runx2 and represses Runx2-mediated trans-activation. Importantly, generation of Trps1(DeltaGT/+);Runx2(+/-) double heterozygous mice rescued the opposite growth plate phenotypes of single mutants, demonstrating the genetic interaction between Trps1 and Runx2 transcription factors. Collectively, these data suggest that skeletal dysplasia in TRPS is caused by dysregulation of chondrocyte and perichondrium development partially due to loss of Trps1 repression of Runx2.
| S-EPMC2710999 | biostudies-literature
Project description:TRPS1 is a GATA-type transcription factor that is closely related to human tricho-rhino-phalangeal syndrome (TRPS) types I and III, variants of an autosomal dominant skeletal disorder. During embryonic development, Trps1 represses Sox9 expression and regulates Wnt signaling pathways that determine the number of hair follicles and their normal morphogenesis. In the growth plate, Trps1 regulates chondrocytes condensation, proliferation, and maturation and phalangeal joint formation by functioning downstream of Gdf5 signaling and by targeting at Pthrp, Stat3 and Runx2. Also, Trps1 protein directly interacts with an activated form of Gli3. In embryonic kidneys, Trps1 functions downstream of BMP7 promoting the mesenchymal-to-epithelial transition, and facilitating tubule morphogenesis and ureteric bud branching. Moreover, Trps1 has been found to be closely related to tumorigenesis, invasion, and metastasis in prostate and breast cancers. It is interesting to note that during the development of hair follicles, bones, and kidneys, mutations in Trps1 cause, either directly or through crosstalk with other regulators, a notable change in cell proliferation and cell death. In this review, we will summarize the most recent studies on Trps1 and seek to elucidate the role for Trps1 in apoptotic regulation.
| S-EPMC3972667 | biostudies-literature
Project description:BackgroundTricho-rhino-phalangeal syndrome (TRPS) is a rare autosomal dominant genetic disorder characterized by distinctive craniofacial and skeletal abnormalities, while non-ossifying fibroma (NOF) is a common benign bone tumour in children and adolescents. To date, no case of TRPS coexisting with NOF has been reported. This report presents a 12-year-old girl who had the characteristic features of tricho-rhino-phalangeal syndrome and non-ossifying fibroma with a fibula fracture.Case presentationA 12-year-old girl was admitted to the Department of Endocrinology and Diabetes for evaluation of brachydactyly and a right fibula fracture. Clinical examination revealed sparse scalp hair, a characteristic bulbous pear-shaped nose, and brachydactyly with significant shortening of the fourth metatarsal. Neither intellectual disability nor multiple exostoses were observed. Radiography of both hands showed brachydactyly and cone-shaped epiphyses of the middle phalanges of the digits of both hands with deviation of the phalangeal axis. Genetic analysis of TRPS1 identified a heterozygous germline sequence variant (p.Ala932Thr) in exon 6 in the girl and her father. Approximately 1 month before being admitted to our department, the girl experienced a minor fall and suffered a fracture of the proximal fibula in the right lower limb. The pathological cytological diagnosis of the osteolytic lesion was NOF. Ten months following the surgery, the lesion on the proximal fibula of the girl disappeared.ConclusionsIn conclusion, the present study is the first to report a rare case of NOF with a pathologic fracture in the fibula of a girl with TRPS. The identification of a missense mutation, (p.Ala932Thr), in exon 6 of TRPS1 in this kindred further suggested that the patient had type I TRPS and indicated that mutations in this exon may be correlated with more pronounced features of the syndrome. Radiological techniques and genetic analysis played key roles in the definitive diagnosis.
| S-EPMC6292130 | biostudies-literature
Project description:BackgroundOkur-Chung neurodevelopmental syndrome (OCNDS) and tricho-rhino-phalangeal syndrome type I (TRPSI) are rare Mendelian diseases. OCNDS is caused by CSNK2A1 gene variants and TRPSI is caused by the TRPS1gene. However, to have two Mendelian diseases in one patient is even rarer.Case presentationA 6-year-10-month-old boy characterized by special facial features, short stature and mental retardation was referred to our pediatric endocrinology department. Whole-exome sequencing (WES) was done to detect the molecular basis of his disease. This patient was confirmed to carry two variants in the CSNK2A1 gene and one in the TRPS1 gene. The variant in the CSNK2A1 gene was vertically transmitted from his father, and the variant in TRPS1 gene from his mother. These two variants are classified as pathogenic and the causes of the presentation in this child. This patient's father and mother have subsequently been diagnosed as having OCNDS and TRPSI respectively.ConclusionThis is the first reported case of a dual molecular diagnosis of tricho-rhino-phalangeal syndrome type I and Okur-Chung neurodevelopmental syndrome in the same patient. This patient is the first published example of vertical transmission of this recurrent CSN2A1 variant from parent to child. A novel variant in the TRPS1 gene that is pathogenic was also identified. In conclusion, identification of the variants in this patient expands the phenotypes and molecular basis of dual Mendelian diseases.
| S-EPMC7398275 | biostudies-literature