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Title
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Caffey disease is associated with distinct arginine to cysteine substitutions in the proα 1(I) chain of type I procollagen
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Author
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Abstract
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| Purpose Infantile Caffey disease is a rare disorder characterized by acute inflammation with subperiosteal new bone formation, associated with fever, pain, and swelling of the overlying soft tissue. Symptoms arise within the first weeks after birth and spontaneously resolve before the age of two years. Many, but not all, affected individuals carry the heterozygous pathogenic COL1A1 variant (c.3040C>T, p.(Arg1014Cys)). Methods We sequenced COL1A1 in 28 families with a suspicion of Caffey disease and performed ultrastructural, immunocytochemical, and biochemical collagen studies on patient skin biopsies. Results We identified the p.(Arg1014Cys) variant in 23 families and discovered a novel heterozygous pathogenic COL1A1 variant (c.2752C>T, p.(Arg918Cys)) in five. Both arginine to cysteine substitutions are located in the triple helical domain of the pro alpha 1(I) procollagen chain. Dermal fibroblasts (one patient with p.(Arg1014Cys) and one with p.(Arg918Cys)) produced molecules with disulfide-linked pro alpha 1(I) chains, which were secreted only with p.(Arg1014Cys). No intracellular accumulation of type I procollagen was detected. The dermis revealed mild ultrastructural abnormalities in collagen fibril diameter and packing. Conclusion The discovery of this novel pathogenic variant expands the limited spectrum of arginine to cysteine substitutions in type I procollagen. Furthermore, it confirms allelic heterogeneity in Caffey disease and impacts its molecular confirmation. |
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Language
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English
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Source (journal)
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Genetics in medicine. - Philadelphia, Pa.
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Publication
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London
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Springernature
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2021
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ISSN
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1098-3600
1530-0366
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DOI
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10.1038/S41436-021-01274-Y
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Volume/pages
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23
:12
(2021)
, p. 2378-2385
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ISI
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000673183300001
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Pubmed ID
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34272483
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Full text (Publisher's DOI)
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