title: CD59 deficiency is associated with chronic hemolysis and childhood relapsing immune-mediated polyneuropathy.
abstract: CD59 deficiency is a common finding in RBCs and WBCs in patients with chronic hemolysis suffering from paroxysmal nocturnal hemoglobinuria in which the acquired mutation in the PIGA gene leads to membrane loss of glycosylphosphatidylinositol-anchored membrane proteins, including CD59. The objective of the present study was to elucidate the molecular basis of childhood familial chronic Coombs-negative hemolysis and relapsing polyneuropathy presenting as chronic inflammatory demyelinating polyradiculoneuropathy in infants of North-African Jewish origin from 4 unrelated families. A founder mutation was searched for using homozygosity mapping followed by exome sequencing. The expression of CD59, CD55, and CD14 was examined in blood cells by flow cytometry followed by Western blot of the CD59 protein. A homozygous missense mutation, p.Cys89Tyr in CD59, was identified in all patients. The mutation segregated with the disease in the families and had a carrier rate of 1:66 among Jewish subjects of North-African origin. The mutated protein was present in the patients' cells in reduced amounts and was undetectable on the membrane surface. Based on the results of the present study, we conclude that the Cys89Tyr mutation in CD59 is associated with a failure of proper localization of the CD59 protein in the cell surface. This mutation is manifested clinically in infancy by chronic hemolysis and relapsing peripheral demyelinating disease.
authors.affiliation: Neuropediatric Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Nevo
authors.forename: Bruria
authors.initials: B
authors.lastname: Ben-Zeev
authors.forename: Adi
authors.initials: A
authors.lastname: Tabib
authors.forename: Rachel
authors.initials: R
authors.lastname: Straussberg
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.forename: Zamir
authors.initials: Z
authors.lastname: Shorer
authors.forename: Aviva
authors.initials: A
authors.lastname: Fattal-Valevski
authors.forename: Asaf
authors.initials: A
authors.lastname: Ta-Shma
authors.forename: Sharon
authors.initials: S
authors.lastname: Aharoni
authors.forename: Malcolm
authors.initials: M
authors.lastname: Rabie
authors.forename: Shamir
authors.initials: S
authors.lastname: Zenvirt
authors.forename: Hanoch
authors.initials: H
authors.lastname: Goldshmidt
authors.forename: Yakov
authors.initials: Y
authors.lastname: Fellig
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.forename: Dror
authors.initials: D
authors.lastname: Mevorach
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
mesh_terms: D017668:Age of Onset; D000595:Amino Acid Sequence; D000743:Anemia, Hemolytic / Q000097:blood / Q000134:cerebrospinal fluid / Q000208:ethnology / Q000235:genetics*; D018957:CD59 Antigens / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D005260:Female; D018703:Founder Effect; D006456:Hemoglobinuria / Q000097:blood / Q000134:cerebrospinal fluid / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D007223:Infant; D007585:Jews / Q000235:genetics; D008002:Libya / Q000208:ethnology; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D008969:Molecular Sequence Data; D009018:Morocco / Q000208:ethnology; D020125:Mutation, Missense; D010375:Pedigree; D017354:Point Mutation; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating / Q000097:blood / Q000134:cerebrospinal fluid / Q000208:ethnology / Q000235:genetics*; D021381:Protein Transport
chemical_list: D018957:CD59 Antigens; D008565:Membrane Proteins; C051590:CD59 protein, human