Somatic stem cell (SSC) dysfunction is typical for different progeroid phenotypes in mice with genomic DNA repair defects. MtDNA mutagenesis in mice with defective Polg exonuclease activity also leads to progeroid symptoms, by an unknown mechanism. We found that Polg-Mutator mice had neural (NSC) and hematopoietic progenitor (HPC) dysfunction already from embryogenesis. NSC self-renewal was decreased in vitro, and quiescent NSC amounts were reduced in vivo. HPCs showed abnormal lineage differentiation leading to anemia and lymphopenia. N-acetyl-L-cysteine treatment rescued both NSC and HPC abnormalities, suggesting that subtle ROS/redox changes, induced by mtDNA mutagenesis, modulate SSC function. Our results show that mtDNA mutagenesis affected SSC function early but manifested as respiratory chain deficiency in nondividing tissues in old age. Deletor mice, having mtDNA deletions in postmitotic cells and no progeria, had normal SSCs. We propose that SSC compartment is sensitive to mtDNA mutagenesis, and that mitochondrial dysfunction in SSCs can underlie progeroid manifestations.

Meckel syndrome (MKS) is a severe fetal developmental disorder reported in most populations. The clinical hallmarks are occipital meningoencephalocele, cystic kidney dysplasia, fibrotic changes of the liver and polydactyly. Here we report the identification of a gene, MKS1, mutated in MKS families linked to 17q. Mks1 expression in mouse embryos, as determined by in situ hybridization, agrees well with the tissue phenotype of MKS. Comparative genomics and proteomics data implicate MKS1 in ciliary functions.

The RECQL4 helicase gene is a member of the RECQL gene family, mutated in some Rothmund-Thomson syndrome (RTS) patients. Other members of this gene family are BLM mutated in Bloom syndrome, WRN mutated in Werner syndrome and RECQL and RECQL5. All polypeptides encoded by RECQL genes share a central region of seven helicase domains. The function of RECQL4 remains unknown, but based on the domain homology it possesses ATP-dependent DNA helicase activity such as BLM and WRN. Rothmund-Thomson, Bloom and Werner syndromes have overlapping clinical features, of which high predisposition to malignancies is the most remarkable feature. Here we report a fourth syndrome resulting in mutations in the RECQL genes. RAPADILINO syndrome is an autosomal recessive disorder characterized by short stature, radial ray defects and other malformations, as well as infantile diarrhoea, but not by a significant cancer risk. Four mutations in the RECQL4 gene were found in the Finnish patients, the most common mutation representing exon 7 in-frame deletion saving the helicase domain and showing dominant effect over other three nonsense mutations. The tissue expression of Recql4 in mouse well agrees with the tissue symptoms of RAPADILINO. The skeletal malformations in RAPADILINO and RTS patients as well as the high osteosarcoma risk in RTS propose a special role for RECQL4 in bone development.