TCIRG1‐dependent recessive osteopetrosis: Mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA

@article{Susani2004TCIRG1dependentRO,
  title={TCIRG1‐dependent recessive osteopetrosis: Mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA},
  author={Lucia Susani and Alessandra Pangrazio and Cristina Sobacchi and Anna Taranta and Geert R. Mortier and Ravi Savarirayan and Anna Villa and Paul J. Orchard and Paolo Vezzoni and Alberto Albertini and Annalisa Frattini and Franco Pagani},
  journal={Human Mutation},
  year={2004},
  volume={24}
}
Human malignant infantile osteopetrosis (arOP) is a genetically heterogeneous autosomal recessive disorder of bone metabolism. The TCIRG1 gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, is responsible for more than one‐half of the arOP patients. We performed genetic analysis of TCIRG1 in 55 arOP patients including 25 new cases and identified nine novel mutations. The two most frequent mutations, c.1674–1G>A (aberrant… 
Novel c.G630A TCIRG1 mutation causes aberrant splicing resulting in an unusually mild form of autosomal recessive osteopetrosis
TLDR
The results show that the ΔE56 truncated protein is not functional, suggesting that the mild ARO phenotype observed in the patient is likely due to the residual full‐length protein expression.
Novel mutations of TCIRG1 cause a malignant and mild phenotype of autosomal recessive osteopetrosis (ARO) in four Chinese families
TLDR
Five individuals with ARO from four unrelated Chinese families are reported, adding to the wide range of phenotypes of Chinese patients with TCIRG1-dependent ARO and enrich the database of TC IRG1 mutations.
Genetic analysis of autosomal recessive osteopetrosis in Chuvashiya: the unique splice site mutation in TCIRG1 gene spread by the founder effect
TLDR
The haplotype analysis revealed that all OPTB cases in ChUVashians and Marians originated from a single mutational event and the age of the mutation in Chuvashians was estimated to be approximately 890 years.
Characterization of a Novel Alu‐Alu Recombination‐Mediated Genomic Deletion in the TCIRG1 Gene in Five Osteopetrotic Patients
TLDR
A novel genomic deletion in the TCIRG1 gene is described explaining why, in some patients, mutations in only one allele have previously been found, and a possible common ancestral origin for this large deletion is suggested.
Autosomal recessive osteopetrosis: report of 41 novel mutations in the TCIRG1 gene and diagnostic implications
TLDR
The present work strongly contributes to the molecular dissection of TCIRG1-deficient ARO and identifies several protein residues which are fundamental for proton pump function and could thus be the target of future drugs designed to inhibit osteoclast resorptive activity.
As Little as Needed: The Extraordinary Case of a Mild Recessive Osteopetrosis Owing to a Novel Splicing Hypomorphic Mutation in the TCIRG1 Gene†
  • C. Sobacchi, A. Pangrazio, A. Villa
  • Biology, Medicine
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
  • 2014
TLDR
Surprisingly, a novel nucleotide change in intron 15 of the TCIRG1 gene at the homozygous state is identified, leading to the production of multiple aberrant transcripts, but also, more importantly, of a limited amount of the normal transcript, which shows that a low level of normal TCirG1 protein can dampen the clinical presentation of TC IRG1‐dependent ARO.
A patient with TCIRG1‐related infantile osteopetrosis presenting with congenital anomalies: Chance association or a case for pleiotropy?
TLDR
A patient with ARIO caused by a previously described, homozygous mutation in the TCIRG1 gene who was initially referred for evaluation of congenital unilateral limb and kidney malformations is reported on.
Synonymous Mutations Add a Layer of Complexity in the Diagnosis of Human Osteopetrosis
  • E. Palagano, L. Susani, C. Sobacchi
  • Biology
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
  • 2017
TLDR
The possibility that at least in some cases ARO is due to synonymous changes, erroneously considered clinically silent, in the genes already described in literature, is highlighted and carefully reevaluating the sequencing results of these genes when mutations are not found at a first analysis is suggested.
Identification of two novel mutations on CLCN7 gene in a patient with malignant ostopetrosis
TLDR
The unusual clinical presentation observed in this patient with a mild clinical onset evolving towards a more serious clinical picture, is associated to two novel mutations on CLCN7 gene, suggesting that, performing a molecular diagnosis of osteopetrosis with inconsistent clinical presentation these two novels have to be first considered.
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