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CD55-deficiency in Jews of Bukharan descent is caused by the Cromer blood type Dr(a−) variant
The complement system regulator CD55 was initially found to carry the Cromer blood group system antigens, and its complete loss of function was subsequently revealed to cause a severe monogenic gastrointestinal syndrome characterized by protein-losing enteropathy and susceptibility to venous thrombo...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936040/ https://www.ncbi.nlm.nih.gov/pubmed/35314883 http://dx.doi.org/10.1007/s00439-021-02428-3 |
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author | Kurolap, Alina Hagin, David Freund, Tal Fishman, Sigal Zunz Henig, Noa Brazowski, Eli Yeshaya, Josepha Naiman, Tova Pras, Elon Ablin, Jacob N. Baris Feldman, Hagit |
author_facet | Kurolap, Alina Hagin, David Freund, Tal Fishman, Sigal Zunz Henig, Noa Brazowski, Eli Yeshaya, Josepha Naiman, Tova Pras, Elon Ablin, Jacob N. Baris Feldman, Hagit |
author_sort | Kurolap, Alina |
collection | PubMed |
description | The complement system regulator CD55 was initially found to carry the Cromer blood group system antigens, and its complete loss of function was subsequently revealed to cause a severe monogenic gastrointestinal syndrome characterized by protein-losing enteropathy and susceptibility to venous thrombosis. Here we present homozygosity to the CD55 c.596C>T; p.Ser199Leu variant, which was previously described as the Cromer Dr(a−) genotype, in two Bukharan Jewish CD55-deficiency patients with variable disease severity. We confirm that this missense variant causes aberrant splicing and deletion of 44 bp in exon 5, leading to premature termination and low expression of the CD55 protein. Furthermore, Patient 1 exhibited a mildly abnormal B cell immunophenotyping profile. By population screening we established that this variant is highly prevalent in the Bukharan Jewish population, with a carrier frequency of 1:17, suggesting that many similar patients are un- or mis-diagnosed. The phenotypic variability, ranging from abdominal pain when eating a high-fat diet to the full CD55-deficiency phenotype, is likely related to modifiers affecting the proportion of the variant that is able to escape aberrant splicing. Establishing the diagnosis of CD55-deficiency in a timely manner, even in patients with milder symptoms, may have a critical effect on their management and quality-of-life since treatment with the complement inhibitor eculizumab is highly effective in ameliorating disease manifestations. Awareness of founder mutations within certain populations can further guide genetic testing and prevent a diagnostic odyssey, by placing this CD55 variant high on the differential diagnosis. |
format | Online Article Text |
id | pubmed-8936040 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-89360402022-03-22 CD55-deficiency in Jews of Bukharan descent is caused by the Cromer blood type Dr(a−) variant Kurolap, Alina Hagin, David Freund, Tal Fishman, Sigal Zunz Henig, Noa Brazowski, Eli Yeshaya, Josepha Naiman, Tova Pras, Elon Ablin, Jacob N. Baris Feldman, Hagit Hum Genet Original Investigation The complement system regulator CD55 was initially found to carry the Cromer blood group system antigens, and its complete loss of function was subsequently revealed to cause a severe monogenic gastrointestinal syndrome characterized by protein-losing enteropathy and susceptibility to venous thrombosis. Here we present homozygosity to the CD55 c.596C>T; p.Ser199Leu variant, which was previously described as the Cromer Dr(a−) genotype, in two Bukharan Jewish CD55-deficiency patients with variable disease severity. We confirm that this missense variant causes aberrant splicing and deletion of 44 bp in exon 5, leading to premature termination and low expression of the CD55 protein. Furthermore, Patient 1 exhibited a mildly abnormal B cell immunophenotyping profile. By population screening we established that this variant is highly prevalent in the Bukharan Jewish population, with a carrier frequency of 1:17, suggesting that many similar patients are un- or mis-diagnosed. The phenotypic variability, ranging from abdominal pain when eating a high-fat diet to the full CD55-deficiency phenotype, is likely related to modifiers affecting the proportion of the variant that is able to escape aberrant splicing. Establishing the diagnosis of CD55-deficiency in a timely manner, even in patients with milder symptoms, may have a critical effect on their management and quality-of-life since treatment with the complement inhibitor eculizumab is highly effective in ameliorating disease manifestations. Awareness of founder mutations within certain populations can further guide genetic testing and prevent a diagnostic odyssey, by placing this CD55 variant high on the differential diagnosis. Springer Berlin Heidelberg 2022-03-21 2023 /pmc/articles/PMC8936040/ /pubmed/35314883 http://dx.doi.org/10.1007/s00439-021-02428-3 Text en © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. |
spellingShingle | Original Investigation Kurolap, Alina Hagin, David Freund, Tal Fishman, Sigal Zunz Henig, Noa Brazowski, Eli Yeshaya, Josepha Naiman, Tova Pras, Elon Ablin, Jacob N. Baris Feldman, Hagit CD55-deficiency in Jews of Bukharan descent is caused by the Cromer blood type Dr(a−) variant |
title | CD55-deficiency in Jews of Bukharan descent is caused by the Cromer blood type Dr(a−) variant |
title_full | CD55-deficiency in Jews of Bukharan descent is caused by the Cromer blood type Dr(a−) variant |
title_fullStr | CD55-deficiency in Jews of Bukharan descent is caused by the Cromer blood type Dr(a−) variant |
title_full_unstemmed | CD55-deficiency in Jews of Bukharan descent is caused by the Cromer blood type Dr(a−) variant |
title_short | CD55-deficiency in Jews of Bukharan descent is caused by the Cromer blood type Dr(a−) variant |
title_sort | cd55-deficiency in jews of bukharan descent is caused by the cromer blood type dr(a−) variant |
topic | Original Investigation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936040/ https://www.ncbi.nlm.nih.gov/pubmed/35314883 http://dx.doi.org/10.1007/s00439-021-02428-3 |
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