Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant β2-microglobulin gene

doi:10.1073/pnas.0600548103

Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant β₂-microglobulin gene

Departments of *Internal Medicine and
^¶Physiology and Cell Biology, Ohio State University, Columbus, OH 43210;
^†Department of Surgery, University of Wisconsin, Madison, WI 53792; and
^‡Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Contributed by Thomas A. Waldmann, January 20, 2006

Abstract

Two siblings, products of a consanguineous marriage, were markedly deficient in both albumin and IgG because of rapid degradation of these proteins, suggesting a lack of the neonatal Fc receptor, FcRn. FcRn is a heterodimeric receptor composed of a nonclassical MHC class I α-chain and β₂-microglobulin (β₂m) that binds two ligands, IgG and albumin, and extends the catabolic half-lives of both. Eight relatives of the siblings were moderately IgG-deficient. From sera archived for 35 years, we sequenced the two siblings’ genes for the heterodimeric FcRn. We found that, although the α-chain gene sequences of the siblings were normal, the β₂m genes contained a single nucleotide transversion that would mutate a conserved alanine to proline at the midpoint of the signal sequence. Concentrations of soluble β₂m and HLA in the siblings’ sera were <1% of normal. Transfection assays of β₂m-deficient cultured cells with β₂m cDNA indicated that the mutant β₂m supported <20% of normal expression of β₂m, MHC class I, and FcRn proteins. We concluded that a β₂m gene mutation underlies the hypercatabolism and reduced serum levels of albumin and IgG in the two siblings with familial hypercatabolic hypoproteinemia. This experiment of nature affirms our hypothesis that FcRn binds IgG and albumin, salvages both from a degradative fate, and maintains their physiologic concentrations.

Footnotes

^§To whom correspondence may be addressed. E-mail: tawald{at}helix.nih.gov
^‖To whom correspondence may be addressed at:
415 HLRI, 473 West Twelfth Avenue, Columbus, OH 43210.
E-mail: anderson.48{at}osu.edu
** Waldmann, T. A., Miller, E. J. & Terry, W. D. (1968) Clin. Res. 16, 45 (abstr.).
Author contributions: M.A.W., L.D.H., J.K., C.L.B., C.C., S.M., T.A.W., J.M.R., and C.L.A. designed research; M.A.W. and L.D.H. performed research; M.A.W., L.D.H., J.K., C.L.B., C.C., S.M., and T.A.W. contributed new reagents/analytic tools; M.A.W., L.D.H., J.K., C.L.B., C.C., S.M., T.A.W., J.M.R., and C.L.A. analyzed data; and M.A.W., L.D.H., T.A.W., and C.L.A. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

FcRn,

neonatal Fc receptor;

β2m,

β2-microglobulin;

TIBC,

total iron-binding capacity;

%TS,

percent transferrin saturation with iron;

FHH,

familial hypercatabolic hypoproteinemia;

MFI,

mean fluorescence intensity;

wt,

wild type;

mut,

mutant;

MHC I,

MHC class I;

sHLA,

soluble HLA.