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Volume 272, Number 40, Issue of October 3, 1997 pp. 25168-25175
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Human Factor H Deficiency
MUTATIONS IN FRAMEWORK CYSTEINE RESIDUES AND BLOCK IN H PROTEIN SECRETION AND INTRACELLULAR CATABOLISM

(Received for publication, April 17, 1997, and in revised form, June 24, 1997)

Bettina H. Ault , Bela Z. Schmidt , Natalie L. Fowler , Clifford E. Kashtan ^¶ , Alaa E. Ahmed , Beth A. Vogt ^¶ and Harvey R. Colten

From the  Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, ^¶ Department of Pediatrics, the University of Minnesota, Minneapolis, Minnesota 55455, and  Specialty Laboratories, Inc., Santa Monica, California 90404

The synthesis and secretion of factor H, a regulatory protein of the complement system, were studied in skin fibroblasts from an H-deficient child who has chronic hypocomplementemic renal disease. In normal fibroblasts, factor H transcripts of 4.3 and 1.8 kilobase pairs (kb) encode a 155-kDa protein containing short consensus repeat (SCR) domains 1-20 and a 45-kDa protein which contains SCRs 1-7, respectively. The patient's fibroblasts expressed normal amounts of the 4.3- and 1.8-kb messages constitutively and after tumor necrosis factor-/interferon- stimulation. Lysates of [³⁵S]methionine-labeled fibroblasts from the patient contained the 155- and 45-kDa H polypeptides, but secretion of the 155-kDa protein was blocked; the 45-kDa protein was secreted with normal kinetics. The patient's plasma lacked the 155-kDa protein but contained the small form of H. Moreover, in fibroblasts the retained 155-kDa factor H protein was not degraded, even after 12 h. Immunoflourescent staining and confocal microscopic imaging of the patient's fibroblasts indicated that factor H was retained in the endoplasmic reticulum. Sequence analysis of reverse transcription-polymerase chain reaction products (the entire coding region) and genomic DNA revealed a T1679C substitution on one allele and a G2949A substitution on the other (C518R mutation in SCR 9 and C991Y mutation in SCR 16, respectively). Both mutations affect conserved cysteine residues characteristic of SCR modules and therefore predict profound changes in the higher order structure of the 155-kDa factor H protein. These data provide the first description of a molecular mechanism for factor H deficiency and yield important insights into the normal secretory pathway for this and other plasma proteins with SCR motifs.

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