Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1)1–7 in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis1–7. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.
These findings emphasise the importance of deletion analysis in NF1 since frequent monitoring of tumour presence and growth could potentiate early surgical intervention thereby improving patient survival.
We conclude that CRP could be a key parameter for individually guiding the duration of antibiotic treatment in a major subgroup of newborns with suspected bacterial infection. This approach would allow considerably shorter courses of antibiotic therapy.
The occurrence of PV and PONV in patients undergoing surgery under balanced anaesthesia can be predicted with moderate but acceptable accuracy using one of the available risk scores, regardless of local surgical or anaesthesiological circumstances. For clinical practice, we recommend the score published by Koivuranta, since its calculation is very simple.
Segmental progeroid syndromes are rare, heterogeneous disorders
characterized by signs of premature aging affecting more than one tissue or
organ. A prototypic example is the Werner syndrome (WS), caused by biallelic
germline mutations in the Werner helicase gene (WRN). While
heterozygous lamin A/C (LMNA) mutations are found in a few
nonclassical cases of WS, another 10%–15% of patients initially diagnosed
with WS do not have mutations in WRN or LMNA.
Germline POLD1 mutations were recently reported in five
patients with another segmental progeroid disorder: mandibular hypoplasia,
deafness, progeroid features syndrome. Here, we describe eight additional
patients with heterozygous POLD1 mutations, thereby
substantially expanding the characterization of this new example of segmental
progeroid disorders. First, we identified POLD1 mutations in
patients initially diagnosed with WS. Second, we describe POLD1
mutation carriers without clinically relevant hearing impairment or mandibular
underdevelopment, both previously thought to represent obligate diagnostic
features. These patients also exhibit a lower incidence of metabolic
abnormalities and joint contractures. Third, we document postnatal short stature
and premature greying/loss of hair in POLD1 mutation carriers.
We conclude that POLD1 germline mutations can result in a
variably expressed and probably underdiagnosed segmental progeroid syndrome.
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