Rothmund-Thomson Syndrome-like RECQL4 truncating mutations cause a haploinsufficient low bone mass phenotype in mice

Abstract

Rothmund-Thomson Syndrome (RTS) is an autosomal recessive disorder characterized by poikiloderma, sparse or absent hair, and defects in the skeletal system such as bone hypoplasia, short stature, low bone mass, and an increased incidence of osteosarcoma. RTS type 2 patients typically present with germline compound bi-allelic protein-truncating mutations of RECQL4. As existing murine models predominantly employ Recql4 null alleles, we have here attempted to more accurately model the mutational spectrum of RTS by generating mice with patient-mimicking truncating Recql4 mutations. We found that truncating mutations impaired stability and subcellular localization of RECQL4, which translated to a homozygous embryonic lethality and haploinsufficient low bone mass and reduced cortical bone thickness phenotypes. Combination of a truncating mutation with a conditional Recql4 null allele demonstrated that these defects were intrinsic to the osteoblast lineage. However, the truncating mutations did not promote tumorigenesis, even after exposure to irradiation. We also utilized murine Recql4 null cells to assess the impact of a wider range of human RECQL4 mutations using an in vitro complementation assay. We found differential effects of distinct RECQL4 mutations. While some 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 lead to the development of an osteoporosis-like phenotype through defects in early osteoblast progenitors in mice and identify RECQL4 gene dosage as a novel regulator of bone mass.

Comparison of the fertility of tumor suppressor gene-deficient C57BL/6 mouse strains reveals stable reproductive aging and novel pleiotropic gene

“…Indeed, dysregulation of RECQL4 is associated with several human cancers (59). Moreover, a recent study proposed that mice with RECQL4 truncating mutations do not exhibit tumorigenesis even after exposure to ionizing radiation (60), which suggested that RECQL4-deficiency might play an important role in protecting against deleterious effects later in life in mammals (Figure 7B). Further studies are needed to determine whether this effect is also observed in other RECQL4-deficient mice or patients with RTS.…”

Paciente pediátrico con poiquilodermia de inicio temprano

“…Suele iniciar con un eritema malar en el primer trimestre de vida, que se extiende hacia las extremidades, respetando tronco y abdomen; con el tiempo, toma la forma usual de las lesiones cutáneas como hiperpigmentaciones marrones violáceas que rodean zonas hipopigmentadas, siendo esto un patrón reticular. Se presentan telangiectasias permanentes, predominantes en las mejillas (4,6). En ocasiones, puede acompañarse de ampollas que suelen progresar a úlceras, sobre todo en las manos.…”