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Letter re: Neonatal Diabetes Mellitus and Mutation in the HNF-1ß Gene

Department of Pediatrics University of Genoa Institute G. Gaslini 16174 Genoa, Italy

Address correspondence to: Elena D’Amato, Department of Pediatrics, University of Genoa, G. Gaslini Institute, Largo Gaslini 5, 16174 Genoa, Italy. E-mail: edamato{at}village.it.

To the editor:

We have read with great interest the recent paper by Yorifuji et al. (1) in which the authors report two sibs carrying the same heterozygous mutation in the HNF-1ß gene but with discordant phenotype. One girl showed a more complex phenotype, including Permanent Neonatal Diabetes Mellitus (PNDM), never described before as a consequence of this mutation. Several clinical features described in this patient, including hyperglycemia and seizures occurring at 15 d of life and later retardation and epilepsy, are not typical of a HNF-1ß mutation (2); they seem to match better with the clinical phenotypes of patients with PNDM caused by mutation in the KCNJ11 gene (3, 4). Moreover, the other male sib had a major neonatal disease, including a polycystic dysplastic kidney requiring renal transplantation, which is a classical phenotype associated with heterozygous mutations of the HNF-1ß gene (2). We agree with the authors that additional factors including genetic background may influence phenotype expression. To support their hypothesis, the authors stated that a different genotype in the HNF-1 gene, which is known to form a heterodimer with HNF-1ß, was found in the two sibs (the girl was Asn487Ser/WT and the boy was Asn487Ser/Asn487Ser), and they consider it to be the candidate "additional factor." However, this amino acid change is a known polymorphism (5) and, therefore, its presence does not support their hypothesis.

We suggest that the discordance between the clinical features observed in these sibs could be due not to a single heterozygous mutation in HNF-1ß gene, but rather to a combination of genetic defects. Perhaps because it was not known at the time their paper was submitted, the authors were unaware of very recent literature regarding genes causing PNDM, in particular the paper by Gloyn et al. (3). Another Italian patient has been described as affected by PNDM and presenting at 40 d of life hyperglycemia with ketoacidosis. This patient had two mutated genes, carrying heterozygous mutation in both KCNJ11 and GCK genes (4). Consequently, we suggest that the authors perform additional molecular analysis of the KCNJ11 gene in the two patients.

Footnotes

A response to this letter was invited, but the authors of the original article chose not to provide one.

Received May 24, 2005.

References

1. Yorifuji T, Kurokawa K, Mamada M, Imai T, Kawai M, Nishi Y, Shishido S, Hasegawa Y, Nakahata T 2004 Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1ß gene due to germline mosaicism. J Clin Endocrinol Metab 89:2905–2908[Abstract/Free Full Text]
2. Bellanne-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, Clauin S, Beaufils S, Wilhelm JM, Boitard C, Noel LH, Velho G, Timsit J 2004 Clinical spectrum associated with hepatocyte nuclear factor-1ß mutations. Ann Intern Med 140:510–517
3. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT 2004 Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 350:1838–1849[Abstract/Free Full Text]
4. Massa O, Iafusco D, D’Amato E, Gloyn AL, Hattersley AT, Pasquino B, Tonini G, Dammacco F, Zanette G, Meschi F, Porzio O, Bottazzo G, Crino A, Lorini R, Cerutti F, Vanelli M, Barbetti F 2005 Early onset diabetes study group of the Italian Society of Pediatric Endocrinology and Diabetology KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat 25:22–27[CrossRef][Medline]
5. Yamada S, Nishigori H, Onda H, Takahashi K, Kitano N, Morikawa A, Takeuchi T, Takeda J 1997 Mutations in the hepatocyte nuclear factor-1 gene (MODY3) are not a major cause of late-onset NIDDM in Japanese subjects. Diabetes 46:1512–1513[Medline]

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