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In silico identification and three‐dimensional modelling of the missense mutation in ADAMTS 2 in a sheep flock with dermatosparaxis
Author(s) -
Monteagudo Luis V.,
Ferrer Luis M.,
CatalanInsa Elena,
Savva Demetris,
McGuffin Liam J.,
Tejedor Maria T.
Publication year - 2015
Publication title -
veterinary dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.744
H-Index - 60
eISSN - 1365-3164
pISSN - 0959-4493
DOI - 10.1111/vde.12178
Subject(s) - missense mutation , flock , sanger sequencing , biology , genetics , genotyping , in silico , locus (genetics) , mutation , microbiology and biotechnology , genotype , gene , paleontology
Background Dermatosparaxis ( E hlers– D anlos syndrome in humans) is characterized by extreme fragility of the skin. It is due to the lack of mature collagen caused by a failure in the enzymatic processing of procollagen I . We investigated the condition in a commercial sheep flock. Hypothesis/Objectives Mutations in the ADAM metallopeptidase with thrombospondin type 1 motif, 2 ( ADAMTS2 ) locus, are involved in the development of dermatosparaxis in humans, cattle and the dorper sheep breed; consequently, this locus was investigated in the flock. Animals A single affected lamb, its dam, the dam of a second affected lamb and the rams in the flock were studied. Methods DNA was purified from blood, PCR primers were used to detect parts of the ADAMS 2 gene and nucleotide sequencing was performed using S anger's procedure. Skin samples were examined using standard histology procedures. Results A missense mutation was identified in the catalytic domain of ADAMTS 2. The mutation is predicted to cause the substitution in the mature ADAMTS 2 of a valine molecule by a methionine molecule ( V 15 M ) affecting the catalytic domain of the enzyme. Both the ‘sorting intolerant from tolerant’ ( SIFT ) and the P oly P hen‐2 methodologies predicted a damaging effect for the mutation. Three‐dimensional modelling suggested that this mutation may alter the stability of the protein folding or distort the structure, causing the protein to malfunction. Conclusions and clinical importance Detection of the mutation responsible for the pathology allowed us to remove the heterozygote ram, thus preventing additional cases in the flock.