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Published on: July 3, 2020
Rothmund-Thomson Syndrome-Like RECQL4 Truncating Mutations Cause a Haploinsufficient Low-Bone-Mass Phenotype in Mice
Wilson Castillo-Tandazo1,2, Ann E Frazier3,4, Natalie A Sims1,2
1St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
Abstract:
Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder characterized by defects in the skeletal system, such as bone hypoplasia, short stature, low bone mass, and an increased incidence of osteosarcoma. RTS type 2 patients have germ line compound biallelic protein-truncating mutations of RECQL4. As existing murine models employ Recql4 null alleles, we have attempted to more accurately model RTS by generating mice with patient-mimicking truncating Recql4 mutations. Truncating mutations impaired the stability and subcellular localization of RECQL4 and resulted in homozygous embryonic lethality and a haploinsufficient low-bone mass phenotype. Combination of a truncating mutation with a conditional Recql4 null allele demonstrated that the skeletal defects were intrinsic to the osteoblast lineage. However, the truncating mutations did not promote tumorigenesis. We utilized murine Recql4 null cells to assess the impact of human RECQL4 mutations using an in vitro complementation assay. While some mutations created unstable protein products, others altered subcellular localization of the protein. Interestingly, the severity of the phenotypes correlated with the extent of protein truncation. Collectively, our results reveal that truncating RECQL4 mutations in mice lead to an osteoporosis-like phenotype through defects in early osteoblast progenitors and identify RECQL4 gene dosage as a novel regulator of bone mass.
Insights
Rothmund-Thomson syndrome (RTS) involves RECQL4 mutations, causing low bone mass and skeletal defects. This study models RTS using truncating RECQL4 mutations in mice, revealing gene dosage impacts bone mass regulation.
Area of Science:
- Genetics and Molecular Biology
- Skeletal Biology
- Genomic Instability
Background:
- Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder linked to RECQL4 mutations.
- Existing mouse models do not fully replicate patient-specific truncating mutations.
- Understanding RECQL4's role in skeletal development is crucial for RTS pathogenesis.
Purpose of the Study:
- To generate and characterize mouse models with patient-mimicking truncating RECQL4 mutations.
- To investigate the impact of these mutations on skeletal development and osteosarcoma incidence.
- To elucidate the role of RECQL4 gene dosage in bone mass regulation.
Main Methods:
- Generation of mice with truncating Recql4 mutations.
- Homozygous embryonic lethality and haploinsufficient phenotypes were assessed.
- In vitro complementation assays using Recql4-null cells and human RECQL4 mutations.
Main Results:
- Truncating Recql4 mutations impaired protein stability and localization, leading to embryonic lethality.
- Haploinsufficiency resulted in a low-bone mass phenotype, indicating skeletal defects are intrinsic to osteoblasts.
- Tumorigenesis was not promoted by truncating mutations; phenotype severity correlated with truncation extent.
Conclusions:
- Truncating RECQL4 mutations cause an osteoporosis-like phenotype via osteoblast progenitor defects.
- RECQL4 gene dosage is a novel regulator of bone mass.
- Mouse models with truncating mutations offer insights into RTS pathogenesis and RECQL4 function.
