TY - JOUR
T1 - Hyperinsulinism caused by paternal-specific inheritance of a recessive mutation in the sulfonylurea-receptor gene
AU - Glaser, Benjamin
AU - Ryan, Fergus
AU - Donath, Marc
AU - Landau, Heddy
AU - Stanley, Charles A.
AU - Baker, Lester
AU - Barton, David E.
AU - Thornton, Paul S.
PY - 1999/8
Y1 - 1999/8
N2 - Neonatal hyperinsulinism (HI) is a genetic disorder of pancreatic β- cells characterized by failure to suppress insulin secretion in the presence of hypoglycemia, resulting in brain damage or death if not adequately treated. Germline mutations in four genes have been associated with HI. Some patients have focal regions of β-cell proliferation (focal HI). Seventy HI probands in whom at least one SUR-1 mutation was identified were studied. Clinical data from patients with two SUR-1 mutant alleles were compared with those from patients with single paternally inherited mutations. Thirty-seven probands were homozygous or compound heterozygous for SUR-1 mutations. In 33 probands, only a single mutation was identified, and in 31, the parental origin of the proband could be determined; in 29, the mutation was on the paternal allele (P < 0.0002). For three of these, pancreatic tissue was available and showed focal β-cell hyperplasia. DNA extracted from the focal lesion and adjacent normal pancreas revealed loss of the maternal chromosome 11p15, resulting in reduction to homozygosity for the SUR-1 mutation within the focal lesion only. Using the Tdt-mediated dUTP nick end labeling (TUNEL) reaction, apoptotic β-cells were identified exclusively within the focal region. At diagnosis, disease severity was similar in patients with paternally inherited mutations and those with two mutations. For patients who did not undergo surgery, those with only paternal mutations entered clinical remission within 16 ± 6.2 months, compared with 48 ± 23 months for those with two SUR-1 mutations (P = 0.001). In conclusion, we identified a novel mechanism to explain the pathophysiology of focal HI and provide evidence to suggest that this entity may be self-limiting, since affected β-cells undergo apoptosis.
AB - Neonatal hyperinsulinism (HI) is a genetic disorder of pancreatic β- cells characterized by failure to suppress insulin secretion in the presence of hypoglycemia, resulting in brain damage or death if not adequately treated. Germline mutations in four genes have been associated with HI. Some patients have focal regions of β-cell proliferation (focal HI). Seventy HI probands in whom at least one SUR-1 mutation was identified were studied. Clinical data from patients with two SUR-1 mutant alleles were compared with those from patients with single paternally inherited mutations. Thirty-seven probands were homozygous or compound heterozygous for SUR-1 mutations. In 33 probands, only a single mutation was identified, and in 31, the parental origin of the proband could be determined; in 29, the mutation was on the paternal allele (P < 0.0002). For three of these, pancreatic tissue was available and showed focal β-cell hyperplasia. DNA extracted from the focal lesion and adjacent normal pancreas revealed loss of the maternal chromosome 11p15, resulting in reduction to homozygosity for the SUR-1 mutation within the focal lesion only. Using the Tdt-mediated dUTP nick end labeling (TUNEL) reaction, apoptotic β-cells were identified exclusively within the focal region. At diagnosis, disease severity was similar in patients with paternally inherited mutations and those with two mutations. For patients who did not undergo surgery, those with only paternal mutations entered clinical remission within 16 ± 6.2 months, compared with 48 ± 23 months for those with two SUR-1 mutations (P = 0.001). In conclusion, we identified a novel mechanism to explain the pathophysiology of focal HI and provide evidence to suggest that this entity may be self-limiting, since affected β-cells undergo apoptosis.
UR - http://www.scopus.com/inward/record.url?scp=0032790274&partnerID=8YFLogxK
U2 - 10.2337/diabetes.48.8.1652
DO - 10.2337/diabetes.48.8.1652
M3 - Article
SN - 0012-1797
VL - 48
SP - 1652
EP - 1657
JO - Diabetes
JF - Diabetes
IS - 8
ER -