Role of truncating mutations in MME gene in fetomaternal alloimmunisation and antenatal glomerulopathies.

BACKGROUND: Membranous glomerulonephritis is an immune-mediated disease. In a recent case of antenatal membranous glomerulonephritis, we identified neutral endopeptidase (NEP) as the podocyte target antigen of circulating antibodies produced by the mother who failed to express NEP on granulocytes. We aimed to investigate whether the disease could affect other families, to search for mutations in the metallomembrane endopeptidase (MME) gene for NEP, and to analyse the outcome of the antenatal renal insult. METHODS: From three families with a case of neonatal membranous glomerulopathy, we detected mutations by direct sequencing of genomic PCR products. Single nucleotide polymorphism (SNP) analysis was undertaken with five SNPs located in the MME gene. IgG subclasses with anti-NEP activity were determined by western blotting. FINDINGS: In five mothers, we identified two compound heterozygous or homozygous mutations in the MME gene. The first, a 1342C-->T nonsense mutation, was detected in one family. The second, 446delC, was detected in all three families; all chromosomes bearing this mutation had the same alleles for the five SNPs. Severity of neonatal renal disease was determined by the mothers' IgG response to fetal NEP antigens expressed on glomerular podocytes. The oldest affected individual, now aged 20 years, has developed severe chronic renal failure. INTERPRETATION: Truncating mutations in the MME gene are the cause of alloimmunisation during pregnancy. Idiopathic renal failure in early adulthood might be caused by immune-mediated fetal nephron loss. We show that disease caused by fetomaternal alloimmunisation secondary to a genetic defect is not restricted to blood cells. RELEVANCE TO CLINICAL PRACTICE: During pregnancy, the absence of the NEP protein induces an alloimmunisation process against NEP presented by fetal cells, including syncytiotrophoblasts. The fetal podocyte insult and ensuing nephron loss could lead to chronic renal failure in early adulthood. Alloimmunisation against NEP should be considered as a leading cause of membranous glomerulopathy early in life. Concentrations of circulating anti-NEP antibodies should be carefully monitored during subsequent pregnancies, and specific therapeutic approaches developed. This new disease might also account for idiopathic chronic renal failure detected during adolescence, in individuals who can be identified by searching for anti-NEP antibodies in their mother and by MME gene mutation analysis. NEP deficiency should also be considered in patients developing de-novo membranous glomerulopathy after renal transplantation.

[Extra-membranous glomerulonephritis: report of a family and new physiopathological concepts]. / Les glomérulonéphrites extra-membraneuses: histoire d'une famille et nouveaux concepts physiopathologiques.

Membranous glomerulonephritis (MGN) is a major cause of the nephrotic syndrome and chronic renal insufficiency. Studies on the reactivity of nephritogenic antibodies implicated in a case of antenatal MGN led to identify for the first time a target of the immune conflict in glomeruli, neutral endopeptidase (CD10). This enzyme that is restricted to certain tissues, being strongly expressed in the placenta and on glomerular podocytes, is involved in the catabolism of a number of regulatory peptides, particularly those involved in vasomotricity. We showed that the nephritogenic antibodies blocked enzymatic activity and that the mother became immunized at the time of a previous pregnancy because she was neutral endopeptidase-deficient. Two additional families have been identified since then. The pathophysiologic mechanisms that we have unraveled are reminiscent of Rhesus immunization and open up new avenues for therapeutic intervention.

[Renal involvement in autoimmune enteropathies]. / Atteinte rénale des entéropathies auto-immunes.

The authors report on a infant who presented with an auto-immune enteropathy characterized by the association of a protracted diarrhea, a neonatal insulin-dependent diabetes, and a dermatitis and who developed a nephrotic syndrome at 4 months of age. A renal biopsy showed a membranous glomerulonephritis (MGN) with IgG linear deposits along the tubular basement membranes (TMB). By indirect immunofluorescence anti-enterocyte antibodies together with anti-TMB antibodies and anti-renal brush border (BB) antibodies were found in the serum of the patient. The patient received various immunosuppressive drugs that failed to improve the disease. In the course of the disease the anti-TBM antibodies disappeared progressively but the BB antibodies persisted. A review of the literature indicates that renal involvement is not uncommon in auto-immune enteropathy and in 5 cases it has been reported as being characterized by a nephrotic syndrome related to the presence of a MGN. In 4 of these cases MGN was associated with the presence of anti-TBM antibodies and in the remaining one with anti-BB antibodies. This case report shows that in human pathology, auto-antibodies to BB proteins may, as well as in experimental models, be responsible for the development of a MGN. It suggests a close relationship (probably a common epitope) between the renal BB proteins and the proteins of the gut epithelium.