Autosomal recessive hypotrichosis with loose anagen hairs associated with TKFC mutations.

BACKGROUND: Loose anagen hair is a rare form of impaired hair anchorage in which anagen hairs that lack inner and outer root sheaths can be gently and painlessly plucked from the scalp. This condition usually occurs in children and is often self-limiting. A genetic basis for the disorder has been suggested but not proven. A better understanding the aetiology of loose anagen hair may improve prevention and treatment strategies. OBJECTIVES: To identify a possible genetic basis of loose anagen hair using next-generation DNA sequencing and functional analysis of variants identified. METHODS: In this case study, whole-exome sequencing analysis of a pedigree with one affected individual with features of loose anagen hair was performed. RESULTS: The patient was found to be compound heterozygous for two single-nucleotide substitutions in TKFC resulting in the following missense mutations: c.574G> C (p.Gly192Arg) and c.682C> T (p.Arg228Trp). Structural analysis of human TKFC showed that both mutations are located near the active site cavity. Kinetic assays of recombinant proteins bearing either of these amino acid substitutions showed almost no dihydroxyacetone kinase or D-glyceraldehyde kinase activity, and FMN cyclase activity reduced to just 10% of wildtype catalytic activity. CONCLUSIONS: TKFC missense mutations may predispose to the development of loose anagen hairs. Identification of this new biochemical pathobiology expands the metabolic and genetic basis of hypotrichosis.

Understanding the structural details of APOBEC3-DNA interactions using graph-based representations.

Human APOBEC3 (A3; apolipoprotein B mRNA editing catalytic polypeptide-like 3) is a family of seven enzymes involved in generating mutations in nascent reverse transcripts of many retroviruses, as well as the human genome in a range of cancer types. The structural details of the interaction between A3 proteins and DNA molecules are only available for a few family members. Here we use homology modelling techniques to address the difference in structural coverage of human A3 enzymes interacting with different DNA substrates. A3-DNA interfaces are represented as residue networks ("graphs"), based on which features at these interfaces are compared and quantified. We demonstrate that graph-based representations are effective in highlighting structural features of A3-DNA interfaces. By large-scale in silico mutagenesis of the bound DNA chain, we predicted the preference of substrate DNA sequence for multiple A3 domains. These data suggested that computational modelling approaches could contribute in the exploration of the structural basis for sequence specificity in A3 substrate selection, and demonstrated the utility of graph-based approaches in evaluating a large number of structural models generated in silico.