Activating ABCC8 mutants cause hyperglycemia in permanent neonatal diabetes mellitus (PNDM) and transient neonatal DM (TNDM)

Stable Identifier
R-HSA-5683209
Type
Reaction [transition]
Species
Homo sapiens
Compartment
cytosol, extracellular region, plasma membrane
ReviewStatus
5/5
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Activating ABCC8 mutants cause hyperglycemia in permanent neonatal diabetes mellitus (PNDM) and transient neonatal DM (TNDM)
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Neonatal diabetes mellitus (NDM) is a rare condition defined as insulin-requiring hyperglycemia within the first month of life. About half of the neonates have a transient form that resolves at a median age of 3 months whereas the rest have a permanent form of diabetes.

ATP-binding cassette sub-family C member 8 (ABCC8) is a subunit of the beta-cell ATP-sensitive potassium channel (KATP). KATP channels play an important role in the control of insulin release. Elevation of the ATP:ADP ratio closes KATP channels leading to cellular depolarisation, calcium influx and exocytosis of insulin from its storage granules. Defects in ABCC8 can cause dysregulation of insulin secretion resulting in hyperglycemias or hypoglycemias.

Defects in ABCC8 can cause permanent neonatal diabetes mellitus (PNDM; MIM:606176). Wild-type ABCC8 confers a lower open-channel probability (Po) than activating mutations of ABCC8, where overactive KATP channels reduce insulin secretion, resulting in hyperglycemia, diagnosed within the first months of life. PNDM requires lifelong therapy. Mutations causing PNDM include P132L, L213R, N72S, A1185E and E382K (Proks et al. 2006, Babenko et al. 2006, Ellard et al. 2007).

Defects in ABCC8 can also cause transient noenatal diabetes mellitus 2 (TNDM2; MIM:610374). Babies are born with intrauterine growth retardation and present within the first 6 weeks of life with severe failure to thrive, hyperglycemia, and dehydration. The condition usually resolves within the first 6 months after birth but there is a predisposition to type 2 diabetes later in life (Naylor et al. 2011). Activating mutations causing TNDM2 are R1379C and L582V (Babenko et al. 2006). These mutations confer a higher open-channel probability (Po) than wild-type ABCC8, keeping the KATP channel open thus not allow cellular depolarisation to occur with the end result of reduced insulin secretion and hyperglycemia.
Literature References
PubMed ID Title Journal Year
24843477 Genetics and pathophysiology of neonatal diabetes mellitus

Naylor, RN, Greeley, SA, Bell, GI, Philipson, LH

J Diabetes Investig 2011
16613899 A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes

Proks, P, Arnold, AL, Bruining, J, Girard, C, Flanagan, SE, Larkin, B, Colclough, K, Hattersley, AT, Ashcroft, FM, Ellard, S

Hum. Mol. Genet. 2006
16885549 Activating mutations in the ABCC8 gene in neonatal diabetes mellitus

Babenko, AP, Polak, M, Cavé, H, Busiah, K, Czernichow, P, Scharfmann, R, Bryan, J, Aguilar-Bryan, L, Vaxillaire, M, Froguel, P

N. Engl. J. Med. 2006
17668386 Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects

Ellard, S, Flanagan, SE, Girard, CA, Patch, AM, Harries, LW, Parrish, A, Edghill, EL, Mackay, DJ, Proks, P, Shimomura, K, Haberland, H, Carson, DJ, Shield, JP, Hattersley, AT, Ashcroft, FM

Am. J. Hum. Genet. 2007
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Catalyst Activity

ATP-activated inward rectifier potassium channel activity of ABCC8 mutants (PNDM, TNDM2) [plasma membrane]

Physical Entity
ABCC8 mutants (PNDM, TNDM2) [plasma membrane] (Homo sapiens)
Activity
ATP-activated inward rectifier potassium channel activity (GO:0015272)
Functional status

Gain of function of ABCC8 mutants (PNDM, TNDM2) [plasma membrane]

Disease Entity
Status
Disease
Name Identifier Synonyms
neonatal diabetes mellitus DOID:11717 diabetes mellitus syndrome in newborn infant
Cross References
RHEA
Mondo
Authored
Jassal, B  (2015-03-12)
Reviewed
Shukla, S  (2015-09-15)
Created
Jassal, B  (2015-03-12)
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