DNA helicases have essential roles in the maintenance of
genomic -stability. They have achieved even greater prominence with the discovery that mutations in human helicase genes are responsible for a variety of
genetic disorders and are associated with
tumorigenesis. A number of missense mutations in human helicase genes are linked to
chromosomal instability diseases characterized by age-related disease or associated with
cancer, providing incentive for the characterization of molecular defects underlying aberrant cellular phenotypes. In this chapter, we discuss some examples of clinically relevant missense mutations in various human
DNA helicases, particularly those of the
Iron-
Sulfur cluster and RecQ families. Clinically relevant mutations in the XPD helicase can lead to
Xeroderma pigmentosum, Cockayne's syndrome,
Trichothiodystrophy, or
COFS syndrome. FANCJ mutations are associated with
Fanconi anemia or
breast cancer. Mutations of the Fe-S helicase ChlR1 (DDX11) are linked to Warsaw Breakage syndrome. Mutations in the
RecQ helicases BLM and WRN are linked to the
cancer-prone disorder
Bloom's syndrome and
premature aging condition
Werner syndrome, respectively. RECQL4 mutations can lead to
Rothmund-Thomson syndrome,
Baller-Gerold syndrome, or RAPADILINO. Mutations in the Twinkle mitochondrial helicase are responsible for several neuromuscular degenerative disorders. We will discuss some insights gained from biochemical and genetic studies of helicase variants, and highlight some hot areas of helicase research based on recent developments.