RECQL4 encodes a member of the RecQ helicase family of proteins; helicase enzymes are responsible for unwinding double stranded DNA. RECQL4 helicase activity relies on ATP hydrolysis, and unwinds DNA for the purpose of replication, base excision repair, double stranded break repair, recombination, as well as telomere maintenance and mitochondrial DNA protection.
RECQL4 dysfunction is associated with autosomal recessive Rothmund-Thomson Syndrome, Rapadilino syndrome, Baller-Gerold syndrome, as well as predisposition to cancer.
RECQL4 is located on the q arm of chromosome 8 and is 6,562 bases long ranging from 144,511,284 to 144,517,845 base pairs pter. It contains 21 exons and translates into a 1208aa long protein with a molecular weight of 133,077Da. 4 paralogs of this gene exist. The protein exhibits a unique Sld-2 like N-terminal domain thought to be essential for initiating DNA replication, as well as helicase domains with 7 nucleic acid binding consensus motifs. RECQL4 is variably expressed in the nucleus in most tissues. The gene is most expressed in the testis, thymus, skin, and bone marrow. Protein expression is most abundant in dividing cells and in the lung.
Over 40 loss of function homozygous and compound heterozygous RECQL4 mutations are associated with 60% of Rothmund-Thomson Syndrome (RTS) cases; RTS cases are at a high risk of developing osteosarcoma. RECQL4 is the only gene linked to RTS; cytogenetic abnormalities in chromosome 8 including partial duplication, trisomy, and tetrasomy were reported in other RTS cases. Pathogenic RECQL4 variants additionally cause Rapadilino syndrome and Baller-Gerold syndrome both of which share overlapping features with RTS.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing (WES) in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism (IEM) and other genetic disorders. Among the cohort with non-IEM related genetic disorders in whom mutational pathogenicity was confirmed, 1 patient was diagnosed with Rothmund-Thomson syndrome. A novel homozygous nonsense transversion in RECQL4 (c.1000G>T; p.Glu334ter) was identified as the cause.
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