Correspondence

Mutant Neurogenin-3 in Congenital Malabsorptive Diarrhea

N Engl J Med 2007; 356:1781-1782April 26, 2007

Article

To the Editor:

In the report by Wang et al. (July 20 issue)1 about mutant neurogenin-3 in patients with congenital malabsorptive diarrhea, patients with the R93L and R107S mutations of the neurogenin-3 gene (NEUROG3) had congenital diarrhea and sparse enteroendocrine cells. They did not have diabetes at birth and, by inference, had insulin-producing cells in the islets of Langerhans. In contrast, mice deficient in Neurog3 have neonatal diabetes due to a total lack of beta cells.2 Wang et al. therefore suggest that a putative unidentified factor can partially compensate for a lack of NEUROG3 in the developing human pancreas.1 We report that the R93L and R107S mutations are not null but hypomorphic and are capable of inducing endocrine development when expressed in the primitive-gut endoderm of chicken embryos (Figure 1AFigure 1Endocrine-Inducing Activity of Wild-Type and Mutant NEUROG3 in Chicken Embryos.; see also Figure 1 in the Supplementary Appendix, available with the full text of this letter at www.nejm.org) and in a cell-based assay (Figure 1B). We suggest that this residual activity, together with the ability of pancreatic beta cells to proliferate in response to increased demand for insulin,4 can explain the presence of a beta-cell mass that is sufficient to preclude glucose intolerance, at least in young patients carrying these mutations.

Jan N. Jensen, Ph.D.
Louise C. Rosenberg, M.Sc.
Jacob Hecksher-Sørensen, Ph.D.
Palle Serup, Ph.D.
Hagedorn Research Institute, 2820 Gentofte, Denmark

4 References

1. 1

   Wang J, Cortina G, Wu SV, et al. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med 2006;355:270-280
   Full Text | Web of Science | Medline

2. 2

   Gradwohl G, Dierich A, LeMeur M, Guillemot F. Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci U S A 2000;97:1607-1611
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   Grapin-Botton A, Majithia AR, Melton DA. Key events of pancreas formation are triggered in gut endoderm by ectopic expression of pancreatic regulatory genes. Genes Dev 2001;15:444-454
   CrossRef | Web of Science | Medline

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   Kulkarni RN, Jhala US, Winnay JN, Krajewski S, Montminy M, Kahn CR. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Invest 2004;114:828-836
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Author/Editor Response

We agree with Jensen et al. that the R107S and R93L mutations of NEUROG3 may be hypomorphic, rather than true null mutants. They and we both used functional assays that rely on exogenously administered vectors; the discrepancy between our data and theirs illustrates the limitations of this type of assay.1

The NEUROG3 mutants were sufficiently impaired to disrupt the genesis of enteroendocrine cells throughout the small and large bowel, yet they presumptively retained at least a sufficient beta-cell mass to sustain euglycemia, despite prolonged intravenous glucose infusion.1,2 This discrepancy may be explained by the binding of NEUROG3 to specific nuclear cofactors in intestinal progenitor cells that are disrupted by the mutations but are not required for the generation of beta cells. Alternatively, a redundant, NEUROG3-independent pathway that is unique to humans may result in the production of at least some islet and beta cells.

Further insight into the effects of NEUROG3 on the development of enteroendocrine and beta cells could may be provided by the study of additional Neurog3-targeted mice (e.g., mice carrying the R107S or R93L mutations) or the identification of other types of NEUROG3 mutations in children with “enteric anendocrinosis.”

Martín G. Martín, M.D.
S. Vincent Wu, Ph.D.
Galen Cortina, M.D., Ph.D.
UCLA School of Medicine, Los Angeles, CA 90095
mmartin@mednet.ucla.edu

2 References

1. 1

   Carey M, Smale ST. Transcriptional regulation in eukaryotes: concepts, strategies, and techniques. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2000.
   

2. 2

   Bjerknes M, Cheng H. Neurogenin 3 and the enteroendocrine cell lineage in the adult mouse small intestinal epithelium. Dev Biol 2006;300:722-735
   CrossRef | Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   Aaron Turkish, Sohail Z. Husain. 2011. Pancreatic Development. , 878-889.
   CrossRef

2. 2

   Louise C. Rosenberg, Merete L. Lafon, Jesper Karup Pedersen, Hani Yassin, Jan Nygaard Jensen, Palle Serup, Jacob Hecksher-Sørensen. (2010) The transcriptional activity of Neurog3 affects migration and differentiation of ectopic endocrine cells in chicken endoderm. Developmental Dynamics 239:7, 1950-1966
   CrossRef

3. 3

   Kristen D. McKnight, Pei Wang, Seung K. Kim. (2010) Deconstructing Pancreas Development to Reconstruct Human Islets from Pluripotent Stem Cells. Cell Stem Cell 6:4, 300-308
   CrossRef

4. 4

   Stuart B. Smith, Hui-Qi Qu, Nadine Taleb, Nina Y. Kishimoto, David W. Scheel, Yang Lu, Ann-Marie Patch, Rosemary Grabs, Juehu Wang, Francis C. Lynn, Takeshi Miyatsuka, John Mitchell, Rina Seerke, Julie Désir, Serge Vanden Eijnden, Marc Abramowicz, Nadine Kacet, Jacques Weill, Marie-Ève Renard, Mattia Gentile, Inger Hansen, Ken Dewar, Andrew T. Hattersley, Rennian Wang, Maria E. Wilson, Jeffrey D. Johnson, Constantin Polychronakos, Michael S. German. (2010) Rfx6 directs islet formation and insulin production in mice and humans. Nature 463:7282, 775-780
   CrossRef

5. 5

   R. Scharfmann, B. Duvillie, V. Stetsyuk, M. Attali, G. Filhoulaud, G. Guillemain. (2008) β-cell development: the role of intercellular signals. Diabetes, Obesity and Metabolism 10, 195-200
   CrossRef

6. 6

   T. Sugiyama, S. K. Kim. (2008) Fluorescence-activated cell sorting purification of pancreatic progenitor cells. Diabetes, Obesity and Metabolism 10, 179-185
   CrossRef