Mutations in the Sulfonylurea Receptor Gene in Familial Persistent Hyperinsulinemic Hypoglycemia of Infancy

Thomas, Peedikayil E.; Cote, Gilbert J.; Wohllk, Nelson; Haddad, Bassem R.; Mathew, P. M.; Rabl, Wolfgang; Aguilar‐Bryan, Lydia; Gagel, Robert F.; Bryan, Joseph

doi:10.1126/science.7716548

Cited by 790 publications

(463 citation statements)

References 26 publications

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“…We compared sequences and mutations in ABCC6/MRP6 with ABCC2, ABCC8, ABCC7, and ABCR, which are implicated in, respectively, Dubin-Johnson syndrome, familial persistent hyperinsulinaemic hypoglycaemia of infancy, cystic fibrosis, and Stargardt disease or perhaps even age-related macula degeneration. [23][24][25][26][27] As we expected, a number of similar mutations occurred in conserved regions of the ABC proteins or even in the same conserved residues. In all proteins, a large number of mutations implicated in disease occurred in the NBF1 and NBF2 domains.…”

Section: Pxe Mutations -Functional Consequencesmentioning

confidence: 76%

ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum

Plomp

Wijnholds

et al. 2003

Eur J Hum Genet

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Pseudoxanthoma elasticum (PXE) is a hereditary disease characterized by progressive dystrophic mineralization of the elastic fibres. PXE patients frequently present with skin lesions and visual acuity loss. Recently, we and others showed that PXE is caused by mutations in the ABCC6/MRP6 gene. However, the molecular pathology of PXE is complicated by yet unknown factors causing the variable clinical expression of the disease. In addition, the presence of ABCC6/MRP6 pseudogenes and multiple ABCC6/MRP6-associated deletions complicate interpretation of molecular genetic studies. In this study, we present the mutation spectrum of ABCC6/MRP6 in 59 PXE patients from the Netherlands. We detected 17 different mutations in 65 alleles. The majority of mutations occurred in the NBF1 (nucleotide binding fold) domain, in the eighth cytoplasmatic loop between the 15th and 16th transmembrane regions, and in NBF2 of the predicted ABCC6/MRP6 protein. The R1141X mutation was by far the most common mutation identified in 19 (32.2%) patients. The second most frequent mutation, an intragenic deletion from exon 23 to exon 29 in ABCC6/MRP6, was detected in 11 (18.6%) of the patients. Our data include 11 novel ABCC6/MRP6 mutations, as well as additional segregation data relevant to the molecular pathology of PXE in a limited number of patients and families. The consequences of our data for the molecular pathology of PXE are discussed.

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Section: Pxe Mutations -Functional Consequencesmentioning

confidence: 76%

ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum

Plomp

Wijnholds

et al. 2003

Eur J Hum Genet

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“…Loss of function of the pancreatic islet K ATP channel, because of mutation of either the SUR1 or Kir6.2 subunit (11)(12)(13)(14), has been demonstrated to lead to persistent hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder characterized by unregulated insulin secretion and severe hypoglycemia (15). Disease phenotypes have not yet been assigned to the other K ATP channels.…”

Section: Atp-sensitive Potassium (K Atp )mentioning

confidence: 99%

A Novel Sulfonylurea Receptor Family Member Expressed in the Embryonic Drosophila Dorsal Vessel and Tracheal System

Nasonkin¹,

Alikaşifoğlu²,

Ambrose³

et al. 1999

Journal of Biological Chemistry

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Sulfonylurea receptors (SURx) are required subunits of the ATP-sensitive potassium channel. SURx alone is electrophysiologically inert. However, when SURx is combined with an inward rectifier Kir6.2 subunit, ATPsensitive potassium channel activity is generated. We report the identification, characterization, and localization of Dsur, a novel Drosophila gene that is highly related to the vertebrate SUR family. The Dsur coding sequence contains structural features characteristic of the ABC transporter family and, in addition, harbors 1.7 kilobases of a distinctive sequence that does not share homology with any known gene. When Dsur alone is expressed in Xenopus oocytes glibenclamide-sensitive potassium channel activity occurs. During Drosophila embryogenesis, the Dsur gene is specifically expressed in the developing tracheal system and dorsal vessel. Studies of the Drosophila genome support that only a single Dsur gene is present. Our data reveal conservation of glibenclamide-sensitive potassium channels in Drosophila and suggest that Dsur may play an important role during Drosophila embryogenesis. The lack of gene duplication in the Drosophila system provides a unique opportunity for functional studies of SUR using a genetic approach.

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“…Some ABC transporters function as multidrug efflux pumps in both prokaryotes and eukaryotes, and overexpression of the mammalian multidrug resistance protein MDR is sometimes responsible for multidrug resistance after chemotherapy in human cancer (2). Several human diseases have been traced to ABC proteins, including cystic fibrosis, hyperinsulinemia, and macular dystrophy (1,(3)(4)(5), making it important to understand their mechanism of action. The maltose transport system, one of at least 50 such systems in Escherichia coli (6), is well characterized both genetically and biochemically and provides an excellent model system for study of the ABC family (7).…”

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confidence: 99%

Trapping the transition state of an ATP-binding cassette transporter: Evidence for a concerted mechanism of maltose transport

Chen¹

2001

Proceedings of the National Academy of Sciences

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High-affinity uptake into bacterial cells is mediated by a large class of periplasmic binding protein-dependent transport systems, members of the ATP-binding cassette superfamily. In the maltose transport system of Escherichia coli, the periplasmic maltose-binding protein binds its substrate maltose with high affinity and, in addition, stimulates the ATPase activity of the membrane-associated transporter when maltose is present. Vanadate inhibits maltose transport by trapping ADP in one of the two nucleotidebinding sites of the membrane transporter immediately after ATP hydrolysis, consistent with its ability to mimic the transition state of the ␥-phosphate of ATP during hydrolysis. Here we report that the maltose-binding protein becomes tightly associated with the membrane transporter in the presence of vanadate and simultaneously loses its high affinity for maltose. These results suggest a general model explaining how ATP hydrolysis is coupled to substrate transport in which a binding protein stimulates the ATPase activity of its cognate transporter by stabilizing the transition state.A TP binding cassette (ABC) transporters are found in each of the phylogenetic kingdoms (1). ABC proteins have been identified that function in an increasing variety of uptake and efflux functions, including nutrient transport, protein and peptide transport, polysaccharide transport, and ion transport. Some ABC transporters function as multidrug efflux pumps in both prokaryotes and eukaryotes, and overexpression of the mammalian multidrug resistance protein MDR is sometimes responsible for multidrug resistance after chemotherapy in human cancer (2). Several human diseases have been traced to ABC proteins, including cystic fibrosis, hyperinsulinemia, and macular dystrophy (1, 3-5), making it important to understand their mechanism of action. The maltose transport system, one of at least 50 such systems in Escherichia coli (6), is well characterized both genetically and biochemically and provides an excellent model system for study of the ABC family (7). It consists of a periplasmic maltose-binding protein (MBP) and a multisubunit ABC transporter (MalFGK 2 ) containing two membrane integral subunits (MalF and MalG) and two copies of a peripheral subunit (MalK) that hydrolyzes ATP (7,8). MBP functions as the primary receptor for maltose, undergoing a conformational change to encapsulate the sugar and generate a high-affinity protein-ligand complex (9, 10). Maltose-loaded MBP then interacts with MalFGK 2 to stimulate ATP hydrolysis by MalK (11) and initiate the transport process. The mechanism by which MBP stimulates ATP hydrolysis is unknown, nor is it known how maltose is transferred from the high-affinity site in MBP to MalFGK 2 .We believe that many of these details can be elucidated by stabilizing and characterizing intermediates in the transport pathway. Vanadate, an analogue of inorganic phosphate, acts as a potent inhibitor of many ATPases, presumably because it can mimic the transition state for the ␥-phosphate of ATP during...

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Mutations in the Sulfonylurea Receptor Gene in Familial Persistent Hyperinsulinemic Hypoglycemia of Infancy

Cited by 790 publications

References 26 publications

ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum

ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum

A Novel Sulfonylurea Receptor Family Member Expressed in the Embryonic Drosophila Dorsal Vessel and Tracheal System

Trapping the transition state of an ATP-binding cassette transporter: Evidence for a concerted mechanism of maltose transport

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