Figure 1
adapted from the human reference amino acid sequence (NP_003174.3). Red arrows show the position corresponding to variants detected in patients in a compound heterozygous state and both parents in a heterozygous state. CANDIS conserved ADAM17 dynamic interaction sequence, MPD membrane proximal domain, CT C-terminal cytoplasmic tail, D disintegrin-like domain, M metalloprotease domain, Pro pro-domain, S signal sequence, TM transmembrane domain. Blue bar indicates the cysteine-rich (Cys-rich) region. The ADAM17 precursor (left) is converted into a mature active form (right) through the enzymatic removal of the signal sequence and pro-domain. Activated ADAM17 is trafficked to the cell surface, where shedding of substrates can occur.
(a) Partial sequence chromatograms of exons 14 and 15 of a disintegrin and metalloprotease 17 (ADAM17) in the genomic DNA of patients (II:1 and II:2) and their parents (I:1 and I:2). Nucleotide and corresponding amino acid sequences of WT and mutant ADAM17 are also shown. Numbers indicate transformed codons by single-base substitutions (red arrows). P proband. (b) Partial sequence chromatograms of exons 14 and 15 of ADAM17 in the mRNA of peripheral blood leucocytes from the proband (patient II:1). Both WT and variant alleles were detected at the same level, suggesting that ADAM17 was equally transcribed from both alleles. Numbers indicate transformed codons by single-base substitutions (red arrows). (c) Comparison of partial amino acid sequences of ADAM17 in human (NP_003174.3), chimp (XP_515293.2), rhesus monkey (XP_002799185.1), mouse (NP_033745.4), chicken (NP_001008682.1), Xenopus tropicalis (NP_001182159.1), fugu (XP_011616093.2), zebrafish (Adam17a, NP_955967.1), fruit fly (Tace, NP_733334.1) and Caenorhabditis elegans (adm-4, NP_509318.1). Conserved amino acids are highlighted. Mutated amino acids are shown by red arrowheads. Numbers indicate codons of mutated amino acids. Bar indicates the highly conserved thioredoxin CXXC motif. (d) Schematic representation of ADAM17. Domains are depicted approximately to the scale
