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Article Figures & Data

Figures

  • Figure 1.

    A sketch of the telomerase and H/ACA small nucleolar ribonucleoprotein complexes. sno indicates small nucleolar; RNP, ribonucleoprotein. Based on information from Chen and Greider,13 Wang and Meier,14 Narayanan et al,15 and Dragon et al.16

  • Figure 2.

    Amino acid substitutions in dyskerin. A linear representation of the protein shows the location of the nuclear localization signals (NL) and the TruB and PUA domains. Vertical bars show the positions of the amino acid substitutions. Those in bold are presented in this paper; those underlined are seen in patients with HH; those with asterisks are seen repetitively.

  • Figure 3.

    Box-whisker plots of telomere lengths. DeltaTEL values are shown in a box-whisker plot for 100 healthy subjects, 15 DC patients age 15 years or more (DC ≥ 15y), 17 DC patients age less than 15 years (DC < 15y), 14 DC patients with AA (DC+AA), and 11 patients with HH.

  • Figure 4.

    TERC mutations in the DCR. The 11 TERC mutations that we have identified in patients in the DCR are shown on a sketch of the TERC molecule (based on information from Chen and Greider13). Mutations identified in patients presenting with AA are underlined. The 3 novel mutations are in bold. Arrows indicate point mutations or the location of breakpoints of large deletions; bars, small deletions.

Tables

  • Table 1.

    Patterns of inheritance and the mutation profile in DC

    Pattern of inheritanceDKC1 mutated*TERC mutatedNo mutation identifiedTotal
    X-linked 21 (4) 0 (0) 1 (1) 22 (5)
    Two affected male siblings 11 (3) 1 (0) 7 (1) 19 (4)
    Sporadic affected male 40 (8) 3 (0) 80 (15) 123 (23)
    Autosomal dominant 0 (0) 7 (0) 4 (0) 11 (0)
    Autosomal recessive 0 (0) 0 (0) 18 (9) 18 (9)
    Sporadic affected female 0 (0) 0 (0) 35 (7) 35 (7)
    All 72 (15) 11 (0) 144 (33) 228 (48)
    • Numbers in parentheses refer to the number of families in each category with HH.

    • * All families with only affected males have been screened for DKC1 mutation; of the families with affected females, 27 have been screened for DKC1 mutation, and all of those are negative.

    • All families have been screened for TERC mutation.

    • Includes 2 families in which both parents are asymptomatic and that were initially thought to show autosomal recessive inheritance but are now known to have autosomal dominant DC due to TERC mutations.

  • Table 2.

    Novel DKC1 mutations

    MutationAA substitutionExonFamilyPresentation
    29C>T P10L 2 DCR160 S-DC/HH
    200C>T T67I 4 DCR108 X-DC/HH
    204C>A H68Q 4 DCR187 S-DC/HH
    941A>G K314R 10 DCR163, DCR204 X-DC/HH, S-DC
    1075G>A D359N 11 DCR190 S-DC
    1156G>A A386T 12 DCR216 S-DC/HH
    1223C>T T408I 12 DCR125 X-DC
    1258, 1259AG>TA S420Y 12 DCR217 S-DC
    IVS14 nt 473A>G N/A IVS14 DCR192 S-DC
    • S indicates sporadic case; DC/HH, patients with features of both classic DC and HH syndrome; X, X-linked inheritance; and nt, intronic mutation.

  • Table 3.

    Phenotypic diversity in 28 patients with the A353V dyskerin mutation

    Disease categoryPhenotypeNo. of patients
    1 DC ≥ 15 y 8
    2 DC < 15 y 7
    3 DC + AA 9
    4 HH 4
    • The disease categories are explained in the text, under “Phenotypic diversity in patients with A353V.”

  • Table 4.

    Clinical severity and telomere lengths in patients with DKC1 mutations

    Disease categoryPhenotypeNo. of subjectsMedian deltaTELRange of deltaTEL
    0 Normal 100 0.058 -3.86 to 3.63
    1 DC ≥ 15 y 15 -2.54 -6.0 to 0
    2 DC < 15 y 17 -4.57 -5.84 to -0.32
    3 DC + AA 14 -3.90 -7.54 to -1.03
    4 HH 11 -5.55 -6.64 to -2.18
    • Mann-Whitney test: category 0 deltaTEL versus categories 1 through 4 deltaTEL, P < .001; category 1 versus 2, P = .044; category 1 versus 3, P = .045; category 1 versus 4, P = .012.

  • Table 5.

    Novel TERC mutations

    MutationLocationFamilyPresentation
    79delC Pseudoknot domain DCR207 FAA
    52-55delCTAA Template region DCR209 S-MDS/DC
    48A>G Template region DCR230 S-DC
    • FAA indicates familial aplastic anemia; S, sporadic case; MDS, myelodysplastic syndrome.

  • Table 6.

    TERT mutations in DCR families

    Pattern of inheritanceNo. of subjects screened*Amino acid substitutions(n)Novel synonymous and intronic sequence changes(n)
    Sporadic affected male 26 A279T (5) 1849C>T (2)
    IVS8 nt-88 G>A (1)
    IVS10 nt-10 T>C (1)
    IVS12 nt-10 G>T (1)
    Autosomal dominant 4 None None
    Autosomal recessive 17 F1127L (1) None
    P721R (1)
    Sporadic affected female 27 A279T (2) IVS10 nt-63C>T (1)
    IVS12 nt 74 C>T (1)
    IVS12 nt 79insCG (1)
    • “n” indicates is the number of times each mutation has been observed in this series of 74 patients; and ins, insertion.

    • * TERT screening of 24 of these subjects has been reported previously.

    • The A279T substitution has previously been shown to be polymorphic; the F1127L substitution has also been described previously; the P721R substitution is described in this paper.

    • Previously published synonymous and intronic sequence changes are not included.