CD55 – Protein-losing enteropathy

The complement regulator CD55 encodes decay-accelerating factor, a glycosylphosphatidylinositol-anchored protein that protects host tissues from complement-mediated damage. Loss of CD55 function causes a monogenic gastrointestinal syndrome with protein-losing enteropathy (PLE) and thrombotic complications, termed CHAPLE syndrome. This disorder is catalogued as Protein-losing enteropathy and results from biallelic inactivation of CD55.

Inheritance follows an autosomal recessive pattern with homozygous or compound heterozygous loss-of-function variants. Whole-exome sequencing in 11 unrelated patients identified diverse splice-site, frameshift, nonsense, and missense mutations, each leading to absent CD55 expression and complement dysregulation ([PMID:28657829]). A recurrent missense variant, c.596C>T (p.Ser199Leu), was found homozygous in two Bukharan Jewish kindreds, establishing a founder allele ([PMID:35314883]).

The c.596C>T (p.Ser199Leu) variant induces aberrant splicing with a 44-bp deletion in exon 5, resulting in premature termination and markedly reduced protein levels in patient cells ([PMID:35314883]). Population screening revealed a carrier frequency of 1:17 among Bukharan Jews, correlating with variable expressivity ranging from mild fat-sensitive abdominal pain to full CHAPLE syndrome.

Functional analyses of patient T lymphocytes demonstrate enhanced complement activation, surface C3 deposition, and elevated soluble C5a due to CD55 deficiency, which is reversed by genetic reconstitution of CD55 or treatment with eculizumab ([PMID:28657829]). Intestinal and hepatic biopsy staining confirm absence of CD55 protein. Eculizumab therapy achieves sustained clinical remission with follow-up exceeding 56 months.

No conflicting reports have been published disputing the CD55–PLE association. The concordance of genetic findings with robust functional rescue supports haploinsufficiency leading to unchecked complement-mediated injury in the gut vasculature.

Taken together, these data warrant a Strong clinical validity classification for the CD55–protein-losing enteropathy association. We recommend including CD55 in diagnostic gene panels for early-onset PLE and unexplained thrombotic events. Eculizumab offers a targeted therapeutic option with durable efficacy. Key Take-home: Biallelic CD55 deficiency underlies CHAPLE syndrome, and early genetic diagnosis enables life-saving complement inhibition.

References

• The New England journal of medicine • 2017 • CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. PMID:28657829
• Human genetics • 2023 • CD55-deficiency in Jews of Bukharan descent is caused by the Cromer blood type Dr(a-) variant. PMID:35314883

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