Programme Hospitalier Recherche Clinique, Institut Pasteur, Inserm, French Public Health Agency.

Maturity-onset diabetes of the young (MODY) 5 is caused by mutations in the TCF2 gene encoding the transcription factor hepatocyte nuclear factor-1␤. However, in 60% of the patients with a phenotype suggesting MODY5, no point mutation is detected in TCF2. We have hypothesized that large genomic rearrangements of TCF2 that are missed by conventional screening methods may account for this observation. In 40 unrelated patients presenting with MODY5 phenotype, TCF2 was screened for mutations by sequencing. Patients without mutations were then screened for TCF2 rearrangements by the quantitative multiplex PCR of short fluorescent fragments (QMPSF). Among the 40 patients, the overall detection rate was 70%: 18 had point mutations, 9 had whole-gene deletions, and 1 had a deletion of a single exon. Similar phenotypes were observed in patients with mutations and in subjects with large deletions. These results suggest that MODY5 is more prevalent than previously reported, with one-third of the cases resulting from large deletions of TCF2. Because QMPSF is more rapid and cost effective than sequencing, we propose that patients whose phenotype is consistent with MODY5 should be screened first with the QMPSF assay. In addition, other MODY genes should be screened for large genomic rearrangements. Diabetes 54:3126 -3132, 2005 M aturity-onset diabetes of the young (MODY) is characterized by the occurrence of nonketotic diabetes of early onset, typically before the age of 25, caused by primary insulinsecretion defects and inherited as an autosomal dominant trait. Currently, heterozygous mutations in six different genes have been identified as a cause of MODY. These genes encode the enzyme glucokinase (MODY2 subtype) and the following transcription factors: hepatocyte nuclear factor-4␣ (HNF-4␣; MODY1), HNF-1␣ (TCF1; MODY3), insulin promoter factor 1 (MODY4), HNF-1␤ (TCF2; MODY5), and neurogenic differentiation factor 1 (MODY6) (1).In 20 -40% of the patients presenting with clinical and family history consistent with MODY, no mutation in the known MODY genes are found (2,3). Part of these socalled MODY-X cases may be caused by mutations in still unidentified genes. Alternatively, some MODY-X cases could result from complex molecular alterations in the known MODY genes that are missed by conventional screening methods.This hypothesis is supported by the observation that large genomic rearrangements account for up to 20% of the molecular defects responsible for other monogenic diseases (4 -7). PCR amplification of individual exons followed by sequencing is currently the standard screening method for MODY mutation analysis. However, in the case of large genomic deletions involving one or several exons, this method would yield false-negative results due to the amplification of the single wild-type allele.MODY5 encompasses a wide clinical spectrum comprising diabetes, pancreas atrophy with subclinical exocrine deficiency, progressive nondiabetic nephropathy, kidney and genital malformations, and liver test abnormalities (8). Sequence ...

Induction of allograft-specific tolerance and the detection of a "tolerance" state in recipients under immunosuppression with long-term stable graft function are major challenges in transplantation. Clinical "operational tolerance," defined as stable and acceptable graft function without immunosuppression for years, is a rare event. There is no report on the clinical history of such patients. In this article, we report on the medical history of 10 kidney recipients who display an immunosuppressive drug-free "operational tolerance" for 9.4 ± 5.2 years. Clinical factors that may favor such a tolerant state are underlined. Firstly, most of the patients interrupted immunosuppression over a long time period (until 4 years), which mimics the procedure of intentional immunosuppression weaning following liver transplantation. Secondly, donor age was younger (median 25 years) than the one of the general transplanted population, suggesting that graft quality is one of the conditions favoring "operational tolerance." Moreover, the "operationally tolerant" recipients may be 'low responders' to blood transfusions (PRA 6 ± 5.4%, six blood transfusions). We also show that "operational tolerance" occurs in the presence of anti-donor class II antibodies, as assessed in two patients. Finally, two patients degraded their renal function 9 to 13 years after treatment withdrawal, however only one presented histological lesions of chronic rejection.

†The two first and senior authors contributed equally.We report here on a European cohort of 27 kidney transplant recipients displaying operational tolerance, compared to two cohorts of matched kidney transplant recipients under immunosuppression and patients who stopped immunosuppressive drugs and presented with rejection. We report that a lower proportion of operationally tolerant patients received induction therapy (52% without induction therapy vs. 78.3% [p = 0.0455] and 96.7% [p = 0.0001], respectively), a difference likely due to the higher proportion (18.5%) of HLA matched recipients in the tolerant cohort. These patients were also significantly older at the time of transplantation (p = 0.0211) and immunosuppression withdrawal (p = 0.0002) than recipients who rejected their graft after weaning. Finally, these patients were at lower risk of infectious disease. Among the 27 patients defined as operationally tolerant at the time of inclusion, 19 still display stable graft function (mean 9 ± 4 years after transplantation) whereas 30% presented slow deterioration of graft function. Six of these patients tested positive for pre-graft anti-HLA antibodies. Biopsy histology studies revealed an active immunologically driven mechanism for half of them, associated with DSA in the absence of C4d. This study suggests that operational tolerance can persist as a robust phenomenon, although eventual graft loss does occur in some patients, particularly in the setting of donor-specific alloantibody.