Genetic characterization of the 2 homozygous TERT mutations. (A) Sequence changes in the TERT gene from both families are shown. Direct DNA sequence analysis shows normal, heterozygous, and homozygous patterns, giving rise to the R811C and R901W substitutions as indicated. (B) A schematic representation of the TERT protein indicates the location of the 2 amino acid substitutions. Conserved domains are indicated by the dark purple boxes, while areas of low conservation are in light purple. Characterized heterozygous mutations and the 2 novel homozygous TERT variants are shown above the linear protein. Their respective clinical phenotypes are indicated as follows: HH in bold italics, DC in bold, AA/MDS in normal text, and polymorphic mutations are underlined. (C) Two regions in the RT domain containing the R811C and R901W substitutions have been expanded below and the amino acid sequence for 5 species aligned. The homozygous mutations (underlined italics) are arrowed. The alignment was carried out by MultAlin.⁴⁹  The Entrez TERT protein sequences used are as follows: NP_003210 for human, NP_033380 for mouse, AAG43537 for Xenopus laevis, S53396 for Saccharomyces cerevisiae, and T51517 for Arabidopsis thaliana.⁵⁰  Interestingly, neither amino acid position is highly conserved between the different species. N-DAT/C-DAT indicates N-terminal/C-terminal dissociates activities of telomerase domains; T, telomerase-specific domain; RT, reverse-transcriptase domain; and NES, nuclear export signal domain.