Multiple in silico tools predict phenotypic manifestations in congenital thrombotic thrombocytopenic purpura.
Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare, recessively inherited genetic disorder with varying clinical presentation that is caused by ADAMTS13 mutations. Several studies have found limited associations between ADAMTS13 mutations and cTTP phenotype. The use of in silico tools that examine multiple mutation characteristics may better predict phenotype. We analysed 118 ADAMTS13 mutations found in 144 cTTP patients reported in the literature and examined associations of several mutation characteristics, including N-terminal proximity, the evolutionary conservation of the affected amino acid position, as well as amino acid charge/phosphorylation and genetic codon usage to disease phenotype. Structure-altering mutations were examined for their impact on ADAMTS13 function based on existing ADAMTS13 crystallographic data (AA 77-685). Our in silico data indicate that: (i) The position of the mutation in the N- or C-terminus, (ii) evolutionary conservation and (iii) codon usage of the affected mutation position are associated with disease parameters, such as age of onset, organ damage and fresh frozen plasma prophylaxis. In conclusion, the usage of multiple in silico tools presents a promising strategy in refining predictions for the diverse presentation of cTTP. Enhancing our utilization of in silico tools to find genotype-phenotype associations will create better-tailored approaches for individual patient treatment.
Laboratory of Hemostasis, Division of Hematology, Center for Biologics Evaluation & Research, FDA, Bethesda, MD 20982, USA.
Zachary A
ZA
Hing
Tal
T
Schiller
Andrew
A
Wu
Nobuko
N
Hamasaki-Katagiri
Evi Budo
EB
Struble
Estelle
E
Russek-Cohen
Chava
C
Kimchi-Sarfaty
D051722:ADAM Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000071120:ADAMTS13 Protein; D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D003062:Codon; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010766:Phosphorylation; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood / Q000235:genetics*
D003062:Codon; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human