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.
Recent efforts to sequence human cancer genomes have highlighted that point mutations in genes involved in the epigenetic setting occur in tumor cells. Small cell lung cancer (SCLC) is an aggressive tumor with poor prognosis, where little is known about the genetic events related to its development. Herein, we have identified the presence of homozygous deletions of the candidate histone acetyltransferase KAT6B, and the loss of the corresponding transcript, in SCLC cell lines and primary tumors. Furthermore, we show, in vitro and in vivo, that the depletion of KAT6B expression enhances cancer growth, while its restoration induces tumor suppressor-like features. Most importantly, we demonstrate that KAT6B exerts its tumor-inhibitory role through a newly defined type of histone H3 Lys23 acetyltransferase activity.
The Say-Barber/Biesecker/Young-Simpson (SBBYS) type of the blepharophimosis-mental retardation syndrome group (Ohdo-like syndromes) is a multiple congenital malformation syndrome characterized by vertical narrowing and shortening of the palpebral fissures, ptosis, intellectual disability, hypothyroidism, hearing impairment, and dental anomalies. Mutations of the gene encoding the histone-acetyltransferase KAT6B have been recently identified in individuals affected by SBBYS syndrome. SBBYS syndrome-causing KAT6B mutations cluster in a ~1,700 basepair region in the 3' part of the large exon 18, while mutations located in the 5' region of the same exon have recently been identified to cause the genitopatellar syndrome (GPS), a clinically distinct although partially overlapping malformation-intellectual disability syndrome. Here, we present two children with clinical features of SBBYS syndrome and de novo truncating KAT6B mutations, including a boy who was diagnosed at the age of 4 months. Our results confirm the implication of KAT6B mutations in typical SBBYS syndrome and emphasize the importance of genotype-phenotype correlations at the KAT6B locus where mutations truncating the KAT6B protein at the amino-acid positions ~1,350-1,920 cause SBBYS syndrome.
DNA replication is fundamental for cell proliferation in all organisms. Nonetheless, components of the replisome have been implicated in human disease, and here we report PRIM1 encoding the catalytic subunit of DNA primase as a novel disease gene. Using a variant classification agnostic approach, biallelic mutations in PRIM1 were identified in five individuals. PRIM1 protein levels were markedly reduced in patient cells, accompanied by replication fork asymmetry, increased interorigin distances, replication stress, and prolonged S-phase duration. Consequently, cell proliferation was markedly impaired, explaining the patients' extreme growth failure. Notably, phenotypic features distinct from those previously reported with DNA polymerase genes were evident, highlighting differing developmental requirements for this core replisome component that warrant future investigation.
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