A novel missense mutation in exon 3 of the TRPS1 gene in a patient with a mild phenotype of tricho-rhino-phalangeal syndrome type 1

Torai, Ryotaro; Makino, Teruhiko; Mizawa, Megumi; Shimomura, Yutaka; Shimizu, Tadamichi

doi:10.1684/ejd.2018.3233

Cited by 4 publications

(4 citation statements)

References 6 publications

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“…Mutant plasmids were obtained from 10 ng of wild‐type pCMV6‐AC‐GFP encoding the full length TRPS1 transcript (RG215856: TRPS1 NM_014112 Human Tagged ORF Clone; OriGene, Rockville, MD, USA) by site‐directed mutagenesis using the QuickChange II XL Site‐Directed Mutagenesis kit (Agilent Technologies, Cedar Creek, TX, USA) and 125 ng of mutation‐specific primers to introduce our novel c.343C>T and the c.422C>T variants, the c.2894G>A variant in exon 7 (mutational hot spot located in the NLS2 domain, used as mutated positive control) and the already described variants c.47G>A and c.203A>C (known variants were renamed according to the reference sequence NM_014112; primer sequences available upon request). ( 25 , 26 , 31 ) Transformed ampicillin‐resistant E. coli colonies were recovered from agar plates and expanded over night and plasmids were purified by the Plasmid Plus Maxi Kit (Qiagen, Valencia, CA, USA) and tested by Sanger sequencing. Twenty thousand (20,000) cells/cm 2 of HepG2 and 15,000 cells/cm 2 of L88/5 were grown (each condition was performed in triplicate) until 80% confluence, transfected with 1 μg of wild‐type and mutated pCMV6‐AC‐GFP TRPS1 expression vectors by the Mega Tran 2.0 transfection reagent (OriGene, Rockville, MD, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Nonsense and frameshift variants led to nonsense-mediated mRNA decay and a dominant negative effect, respectively, whereas missense alterations were supposed to alter the interactions with RUNX2 and induce a milder phenotype. (26)(27)(28) The present work aimed to establish, by the use of wholeexome sequencing (WES) and in vitro functional studies, a correct clinical and genetic diagnosis in syndromic patients with AHO-like skeletal malformations. After a review of available clinical data we tried to identify, if present, those phenotypic manifestations useful for an earlier diagnostic definition of mutated patients.…”

Section: Introductionmentioning

confidence: 99%

“…Nonsense and frameshift variants led to nonsense‐mediated mRNA decay and a dominant negative effect, respectively, whereas missense alterations were supposed to alter the interactions with RUNX2 and induce a milder phenotype. ( 26 , 27 , 28 )…”

Section: Introductionmentioning

confidence: 99%

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Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly

Elli

Mattinzoli

Lucca

et al. 2020

Journal of Bone and Mineral Research

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Skeletal disorders, including both isolated and syndromic brachydactyly type E, derive from genetic defects affecting the fine tuning of the network of pathways involved in skeletogenesis and growth-plate development. Alterations of different genes of this network may result in overlapping phenotypes, as exemplified by disorders due to the impairment of the parathyroid hormone/parathyroid hormone-related protein pathway, and obtaining a correct diagnosis is sometimes challenging without a genetic confirmation. Five patients with Albright's hereditary osteodystrophy (AHO)-like skeletal malformations without a clear clinical diagnosis were analyzed by whole-exome sequencing (WES) and novel potentially pathogenic variants in parathyroid hormone like hormone (PTHLH) (BDE with short stature [BDE2]) and TRPS1 (tricho-rhino-phalangeal syndrome [TRPS]) were discovered. The pathogenic impact of these variants was confirmed by in vitro functional studies. This study expands the spectrum of genetic defects associated with BDE2 and TRPS and demonstrates the pathogenicity of TRPS1 missense variants located outside both the nuclear localization signal and the GATA ((A/T)GATA(A/G)-binding zinc-containing domain) and Ikaros-like binding domains. Unfortunately, we could not find distinctive phenotypic features that might have led to an earlier clinical diagnosis, further highlighting the high degree of overlap among skeletal syndromes associated with brachydactyly and AHO-like features, and the need for a close interdisciplinary workout in these rare patients.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly

Elli

Mattinzoli

Lucca

et al. 2020

Journal of Bone and Mineral Research

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“… 1 , 2 On the other hand, missense variants located outside this domain have been reported to cause a mild-to-moderate disease phenotype. 13 , 14 The missense pathogenic TRPS1 variant identified in our study was also in exon 6. Two related patients (P19 and P20) carrying this variant shared the clinical findings including marked craniofacial findings, severe brachydactyly, and short stature, which were consistent with the findings of previously reported patients with the same pathogenic variant.…”

Section: Discussionmentioning

confidence: 56%

The Clinical and Molecular Spectrum of Trichorhinophalangeal Syndrome Types I and II in a Turkish Cohort Involving 22 Patients

Güneş

Usluer

Ülker

et al. 2023

Turk Arch Pediatrics

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Objective: Trichorhinophalangeal syndrome is a rare autosomal dominant disorder characterized by distinctive craniofacial and skeletal abnormalities. This study aimed to delineate the trichorhinophalangeal syndrome phenotype and to compare the clinical and molecular findings between trichorhinophalangeal syndrome types I and II. Materials and Methods: A total of 22 trichorhinophalangeal syndrome patients aged 0.9-45 years from 17 families were enrolled. Nineteen patients were diagnosed with trichorhinophalangeal syndrome I and 3 with trichorhinophalangeal syndrome II. Genetic analyses were made by TRPS1 sequencing and/or chromosomal microarray analyses. Results : A novel frameshift variant (c.531_532del), a known missense variant, and whole-gene deletions were the pathogenic TRPS1 variants detected in trichorhinophalangeal syndrome I. Three trichorhinophalangeal syndrome II patients had large deletions with variable breakpoints involving the TRPS1 - EXT1 interval. All patients had the typical craniofacial findings of trichorhinophalangeal syndrome such as a pear-shaped nose, long philtrum, and thin upper lip, as well as cone-shaped epiphyses. Sparse hair and eyebrows (20/22), short metacarpals and metatarsals (20/22), and small hands (19/22) were common. While craniofacial and limb abnormalities were similar in trichorhinophalangeal syndrome I and II, 3 of 19 trichorhinophalangeal syndrome I patients had mild, and 2 of 3 trichorhinophalangeal syndrome II patients had severe intellectual disability. Three trichorhinophalangeal syndrome II patients including the patient with the EXT1 deletion beginning from exon 2 had exostoses. In trichorhinophalangeal syndrome II, although microdeletion sizes and facial or skeletal features were not correlated, patients with larger deletions had severe intellectual disability. Conclusion: This study has expanded the existing knowledge on the phenotype–genotype spectrum in trichorhinophalangeal syndrome. We suggest including the EXT1 gene partially in the minimal critical region for trichorhinophalangeal syndrome II.

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Analysis of the function, mechanism and clinical application prospect of TRPS1, a new marker for breast cancer

He,

Huang,

Liu

et al. 2024

Gene

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A novel missense mutation in exon 3 of the TRPS1 gene in a patient with a mild phenotype of tricho-rhino-phalangeal syndrome type 1

Cited by 4 publications

References 6 publications

Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly

Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly

The Clinical and Molecular Spectrum of Trichorhinophalangeal Syndrome Types I and II in a Turkish Cohort Involving 22 Patients

Analysis of the function, mechanism and clinical application prospect of TRPS1, a new marker for breast cancer

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