Sian Ellard

Publications of Sian Ellard

• Childhood presentation of COL4A1 mutations.

  Authors: Siddharth Shah, Sian Ellard, Rachel Kneen, Ming Lim, Nigel Osborne, Julia Rankin, Neil Stoodley, Marjo VAN DER Knaap, Andrea Whitney, Philip Jardine

  Developmental medicine and child neurology. 06/2012; 54(6):569-574.

  Aim  To describe the clinical and radiological features of four new families with a childhood presentation of COL4A1 mutation. Method  We retrospectively reviewed the clinical presentation.Aim  To describe the clinical and radiological features of four new families with a childhood presentation of COL4A1 mutation. Method  We retrospectively reviewed the clinical presentation. Investigations included radiological findings and COL4A1 mutation analysis of the four cases. Affected family members were identified. COL4A1 mutation analysis was performed in all index cases and, where possible, in affected family members. Results  The three male and one female index cases presented with recurrent childhood-onset stroke, infantile hemiplegia/spastic quadriplegia, and infantile spasms. Additional features such as congenital cataracts and anterior segment dysgenesis were present. Microcephaly and developmental delay/learning difficulties were present in three cases. Three cases had one or more family member affected in multiple generations, with a total of 11 such individuals identified. The clinical features showed a wide intrafamilial variation. Magnetic resonance imaging (MRI) showed bilateral white matter change in all cases, except in one mutation-positive family member. Unilateral or bilateral porencephaly was present in cases with infantile hemiplegia, and a diagnosis of clinical stroke was supported by the presence of intracerebral haemorrhage. The age at diagnosis was between 1 year and 6 years for the children with presentation in infancy and 12 months after stroke in a 14-year-old male. Three new pathogenic mutations were identified in the COL4A1 gene. Interpretation  COL4A1 mutations can present in children with infantile hemiplegia/quadriplegia, stroke or epilepsy, and a motor disorder. The presence of eye features and white matter change on MRI in childhood can help point towards the diagnosis. Once the diagnosis is made, a careful search can identify affected family members.

• Leucine-sensitive hyperinsulinaemic hypoglycaemia in patients with loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase.

  Authors: Amanda J Heslegrave, Ritika R Kapoor, Simon Eaton, Bernadette Chadefaux, Teoman Ackay, Enver Simsek, Sarah E Flanagan, Sian Ellard, Khalid Hussain

  Orphanet journal of rare diseases. 05/2012; 7(1):25.

  ABSTRACT: BACKGROUND: Loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase (HADH) cause protein sensitive hyperinsulinaemic hypoglycaemia (HH). HADH encodes short chain 3-hydroxacyl-CoAABSTRACT: BACKGROUND: Loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase (HADH) cause protein sensitive hyperinsulinaemic hypoglycaemia (HH). HADH encodes short chain 3-hydroxacyl-CoA dehydrogenase, an enzyme that catalyses the penultimate reaction in mitochondrial beta-oxidation of fatty acids. Mutations in GLUD1 encoding glutamate dehydrogenase, also cause protein sensitive HH (due to leucine sensitivity). Reports suggest a protein-protein interaction between HADH and GDH. This study was undertaken in order to understand the mechanism of protein sensitivity in patients with HADH mutations. METHODS: An oral leucine tolerance test was conducted in controls and nine patients with HADH mutations. Basal GDH activity and the effect of GTP were determined in lymphoblast homogenates from 4 patients and 3 controls. Immunoprecipitation was conducted in patient and control lymphoblasts to investigate protein interactions. RESULTS: Patients demonstrated severe HH (glucose range 1.7-3.2 mmol/l; insulin range 4.8-63.8mU/l) in response to the oral leucine load, this HH was not observed in control patients subjected to the same leucine load. Basal GDH activity andhalf maximal inhibitory concentration of GTP was similar in patients and controls. HADH protein could be co-immunoprecipitated with GDH protein in control samples but not in patient samples. CONCLUSIONS: We conclude that GDH and HADH have a direct protein-protein interaction, which is lost in patients with HADH mutations causing leucine induced HH. This is not associated with loss of inhibitory effect of GTP on GDH (as in patients with GLUD1 mutations). KEYWORDS: Hyperinsulinism, hypoglycaemia, leucine tolerance.

• Systematic Assessment of Etiology in Adults With a Clinical Diagnosis of Young-Onset Type 2 Diabetes Is a Successful Strategy for Identifying Maturity-Onset Diabetes of the Young.

  Authors: Gaya Thanabalasingham, Aparna Pal, Mary P Selwood, Christina Dudley, Karen Fisher, Polly J Bingley, Sian Ellard, Andrew J Farmer, Mark I McCarthy, Katharine R Owen

  Diabetes care. 03/2012;

  OBJECTIVEMisdiagnosis of maturity-onset diabetes of the young (MODY) remains widespread, despite the benefits of optimized management. This cross-sectional study examined diagnostic misclassificationOBJECTIVEMisdiagnosis of maturity-onset diabetes of the young (MODY) remains widespread, despite the benefits of optimized management. This cross-sectional study examined diagnostic misclassification of MODY in subjects with clinically labeled young adult-onset type 1 and type 2 diabetes by extending genetic testing beyond current guidelines.RESEARCH DESIGN AND METHODSIndividuals were selected for diagnostic sequencing if they displayed features atypical for their diagnostic label. From 247 case subjects with clinically labeled type 1 diabetes, we sequenced hepatocyte nuclear factor 1 α (HNF1A) and hepatocyte nuclear factor 4 (HNF4A) in 20 with residual β-cell function ≥3 years from diagnosis (random or glucagon-stimulated C-peptide ≥0.2 nmol/L). From 322 with clinically labeled type 2 diabetes, we sequenced HNF1A and HNF4A in 80 with diabetes diagnosed ≤30 years and/or diabetes diagnosed ≤45 years without metabolic syndrome. We also sequenced the glucokinase (GCK) in 40 subjects with mild fasting hyperglycemia.RESULTSIn the type 1 diabetic group, two HNF1A mutations were found (0.8% prevalence). In type 2 diabetic subjects, 10 HNF1A, two HNF4A, and one GCK mutation were identified (4.0%). Only 47% of MODY case subjects identified met current guidelines for diagnostic sequencing. Follow-up revealed a further 12 mutation carriers among relatives. Twenty-seven percent of newly identified MODY subjects changed treatment, all with improved glycemic control (HbA(1c) 8.8 vs. 7.3% at 3 months; P = 0.02).CONCLUSIONSThe systematic use of widened diagnostic testing criteria doubled the numbers of MODY case subjects identified compared with current clinical practice. The yield was greatest in young adult-onset type 2 diabetes. We recommend that all patients diagnosed before age 30 and with presence of C-peptide at 3 years duration are considered for molecular diagnostic analysis.

• Recessive SLC19A2 mutations are a cause of neonatal diabetes mellitus in thiamine-responsive megaloblastic anaemia.

  Authors: Charles Shaw-Smith, Sarah E Flanagan, Ann-Marie Patch, Juergen Grulich-Henn, Abdelhadi M Habeb, Khalid Hussain, Renata Pomahacova, Krystyna Matyka, Mohamed Abdullah, Andrew T Hattersley, Sian Ellard

  Pediatric diabetes. 02/2012;

  Permanent neonatal diabetes mellitus (PNDM) is diagnosed within the first 6 months of life, and is usually monogenic in origin. Heterozygous mutations in ABCC8, KCNJ11, and INS genes account forPermanent neonatal diabetes mellitus (PNDM) is diagnosed within the first 6 months of life, and is usually monogenic in origin. Heterozygous mutations in ABCC8, KCNJ11, and INS genes account for around half of cases of PNDM; mutations in 10 further genes account for a further 10%, and the remaining 40% of cases are currently without a molecular genetic diagnosis. Thiamine-responsive megaloblastic anaemia (TRMA), due to mutations in the thiamine transporter SLC19A2, is associated with the classical clinical triad of diabetes, deafness, and megaloblastic anaemia. Diabetes in this condition is well described in infancy but has only very rarely been reported in association with neonatal diabetes. We used a combination of homozygosity mapping and evaluation of clinical information to identify cases of TRMA from our cohort of patients with PNDM. Homozygous mutations in SLC19A2 were identified in three cases in which diabetes presented in the first 6 months of life, and a further two cases in which diabetes presented between 6 and 12 months of age. We noted the presence of a significant neurological disorder in four of the five cases in our series, prompting us to examine the incidence of these and other non-classical clinical features in TRMA. From 30 cases reported in the literature, we found significant neurological deficit (stroke, focal, or generalized epilepsy) in 27%, visual system disturbance in 43%, and cardiac abnormalities in 27% of cases. TRMA should be considered in the differential diagnosis of diabetes presenting in the neonatal period.

• Lipoprotein composition in HNF1A-MODY: Differentiating between HNF1A-MODY and Type 2 diabetes.

  Authors: Tim J McDonald, Jane McEneny, Ewan R Pearson, Gaya Thanabalasingham, Magdalena Szopa, Beverley M Shields, Sian Ellard, Katharine R Owen, Maciej T Malecki, Andrew T Hattersley, Ian S Young

  Clinica chimica acta; international journal of clinical chemistry. 02/2012; 413(9-10):927-32.

  The young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. WeThe young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY.

• The heterogeneity of focal forms of congenital hyperinsulinism.

  Authors: Dunia Ismail, Ritika R Kapoor, Virpi V Smith, Michael Ashworth, Oliver Blankenstein, Agostino Pierro, Sarah E Flanagan, Sian Ellard, Khalid Hussain

  The Journal of clinical endocrinology and metabolism. 01/2012; 97(1):E94-9.

  Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia due to unregulated insulin secretion from pancreatic β-cells. Histologically, there are two major subgroups, focal and diffuse.Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia due to unregulated insulin secretion from pancreatic β-cells. Histologically, there are two major subgroups, focal and diffuse. Focal CHI is typically unresponsive to diazoxide and can be cured with surgical removal of the focal lesion. We report on three patients with focal CHI to illustrate the marked clinical, genetic, radiological, and histological heterogeneity. The first two patients had focal CHI due to a paternal (c.3992-9G→A) ABCC8 mutation. One of these patients was fully responsive to a small dose (5 mg/kg · d) of diazoxide, whereas the other patient was medically unresponsive. In both patients, the focal lesions were accurately localized preoperatively by [(18)F]dihydroxyphenylalanine (DOPA) positron emission tomography (PET) and surgically resected. The third patient had a paternally inherited ABCC8 (A1493T) mutation, and the initial [(18)F]DOPA PET scan indicated extensive uptake of DOPA in the body and tail of the pancreas. However, despite surgical resection of the body and tail, this patient continued to have severe CHI. A subsequent [(18)F]DOPA PET scan now showed markedly increased DOPA uptake in the remaining body and head of the pancreas. This focal lesion occupied virtually the whole of the pancreas. conclusions: These three cases illustrate that focal lesions even with the same genotype (c.3992-9G→A) may have a different clinical presentation and that [(18)F]DOPA PET scans in very large focal lesions may be difficult to interpret.

• GATA6 haploinsufficiency causes pancreatic agenesis in humans.

  Authors: Hana Lango Allen, Sarah E Flanagan, Charles Shaw-Smith, Elisa De Franco, Ildem Akerman, Richard Caswell, Jorge Ferrer, Andrew T Hattersley, Sian Ellard

  Nature genetics. 12/2011; 44(1):20-2.

  Understanding the regulation of pancreatic development is key for efforts to develop new regenerative therapeutic approaches for diabetes. Rare mutations in PDX1 and PTF1A can cause pancreaticUnderstanding the regulation of pancreatic development is key for efforts to develop new regenerative therapeutic approaches for diabetes. Rare mutations in PDX1 and PTF1A can cause pancreatic agenesis, however, most instances of this disorder are of unknown origin. We report de novo heterozygous inactivating mutations in GATA6 in 15/27 (56%) individuals with pancreatic agenesis. These findings define the most common cause of human pancreatic agenesis and establish a key role for the transcription factor GATA6 in human pancreatic development.

• Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment.

  Authors: Catherine Quinlan, Katie Guegan, Amaka Offiah, Richard O' Neill, Melanie P Hiorns, Sian Ellard, Detlef Bockenhauer, William Van't Hoff, Aoife M Waters

  Pediatric nephrology (Berlin, Germany). 11/2011; 27(4):581-8.

  Inactivating mutations in phosphate-regulating endopeptidase (PHEX) cause X-linked hypophosphatemic rickets (XLHR) characterized by phosphaturia, hypophosphatemia, bony deformities, and growthInactivating mutations in phosphate-regulating endopeptidase (PHEX) cause X-linked hypophosphatemic rickets (XLHR) characterized by phosphaturia, hypophosphatemia, bony deformities, and growth retardation. We assessed the efficacy of combined calcitriol and orally administered phosphate (Pi) therapy on longitudinal growth in relation to age at treatment onset in a retrospective, single-center review of children with XLHR and documented PHEX mutations. Growth was compared in those who started treatment before (G1; N = 10; six boys) and after (G2; N = 13; five boys) 1 year old. Median height standard deviation score (HSDS) at treatment onset was normal in G1: 0.1 [interquartile range (IR) -1.3 to 0.4) and significantly (p = 0.004) lower in G2 (IR -2.1 (-2.8 to -1.4). Treatment duration was similar [G1 8.5 (4.0-15.2) vs G2 11.9 (6.2-14.3) years; p = 0.56], as were prescribed phosphate and calcitriol doses. Recent HSDS was significantly (p = 0.009) better in G1 [-0.7 (-1.5 to 0.3)] vs G2 [-2.0 (-2.3 to -1.0)]. No effects of gender or genotype on growth could be identified. Children with PHEX-associated XLHR benefit from early treatment and can achieve normal growth. Minimal catchup growth was seen in those who started treatment later. Our findings emphasize the importance of early diagnosis to allow treatment before growth has been compromised.

• Incidence, genetics, and clinical phenotype of permanent neonatal diabetes mellitus in northwest Saudi Arabia.

  Authors: Abdelhadi M Habeb, Mohamed Sf Al-Magamsi, Ihsan M Eid, Mohamed I Ali, Andrew T Hattersley, Khalid Hussain, Sian Ellard

  Pediatric diabetes. 11/2011;

  Habeb AM, Al-Magamsi MSF, Eid IM, Ali MI, Hattersley AT, Hussain K, Ellard S. Incidence, genetics, and clinical phenotype of permanent neonatal diabetes mellitus in northwest Saudi Arabia.Habeb AM, Al-Magamsi MSF, Eid IM, Ali MI, Hattersley AT, Hussain K, Ellard S. Incidence, genetics, and clinical phenotype of permanent neonatal diabetes mellitus in northwest Saudi Arabia. Background: Permanent neonatal diabetes mellitus (PNDM) in European population has an incidence of at least 1 in 260 000 live births and is most commonly due to mutations in KCNJ11 and ABCC8. However, data on this condition in other populations are limited. Objective: To define the incidence, genetic aetiology, and clinical phenotype of PNDM in Al-Madinah region, northwest Saudi Arabia. Methods: Patients with PNDM diagnosed between 2001 and 2010 were identified and clinically phenotyped. Sequencing of KCNJ11, ABCC8, and INS were performed initially on all subjects, and EIF2AK3, GLIS3, SLC2A2, SLC19A2, GCK, IPF1, and NEUROD1 genes were sequenced according to the clinical phenotype. Results: In total, 17 patients from 11 consanguineous families were diagnosed with PNDM and the incidence was 1 in 21 196 live births. Six different mutations in four genes were identified, of which two GLIS3 and one SLC2A2 were novel and no patient had KCNJ11, ABCC8, or INS mutations. Fourteen (82.4%) patients had identifiable genetic aetiology and their PNDM was part of known autosomal-recessive syndromes including Wolcott Rallison (41.1%), neonatal diabetes and hypothyroidism (29.4%), Fanconi-Bickel (5.8%), and thiamine-responsive megaloblastic anaemia (5.8%). Two patients with isolated PNDM and one with intermediate developmental delay, epilepsy and neonatal diabetes had no identifiable cause. Conclusions: Al-Madinah region has the highest reported incidence of PNDM worldwide. In this region with high consanguinity, PNDM has different genetic aetiology and in the majority of cases presents as a part of rare familial autosomal-recessive syndrome rather than in isolation.

• K(ATP) channel mutations in infants with permanent diabetes diagnosed after 6 months of life.

  Authors: Oscar Rubio-Cabezas, Sarah E Flanagan, Annet Damhuis, Andrew T Hattersley, Sian Ellard

  Pediatric diabetes. 10/2011;

  Rubio-Cabezas O, Flanagan SE, Damhuis A, Hattersley AT, Ellard S. K(ATP) channel mutations in infants with permanent diabetes diagnosed after 6 months of life. Background/Objective: Mutations in theRubio-Cabezas O, Flanagan SE, Damhuis A, Hattersley AT, Ellard S. K(ATP) channel mutations in infants with permanent diabetes diagnosed after 6 months of life. Background/Objective: Mutations in the K(ATP) channel genes are the commonest cause of permanent neonatal diabetes. Most patients obtain optimal glycemic control on sulfonylurea treatment. Genetic testing is currently recommended for all infants diagnosed before 6 months of age. We aimed to explore the prevalence of K(ATP) channel diabetes in infants presenting between 6 and 12 months. Methods: The KCNJ11 and ABCC8 genes were sequenced in 115 infants with permanent diabetes diagnosed between 6 and 12 months and in 405 patients presenting before 6 months. Results: Mutations in either gene were identified in 197 patients diagnosed before 6 months (48.6%), three infants diagnosed between 6 and 9 months (4.2%) and none of those diagnosed after 9 months. Two patients diagnosed after 6 months were successfully transferred from insulin to sulfonylureas. Conclusion: K(ATP) channel mutations are an uncommon cause of diabetes in infants presenting after 6 months. However, given the potential clinical benefit from identifying a K(ATP) channel mutation, we recommend that K(ATP) mutation testing should be routinely extended to infants diagnosed up to 9 months.

• Alagille syndrome: pathogenesis, diagnosis and management.

  Authors: Peter D Turnpenny, Sian Ellard

  European journal of human genetics : EJHG. 09/2011; 20(3):251-7.

  Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is a multisystem disorder due to defects in components of the Notch signalling pathway, most commonly due to mutation in JAG1 (ALGSAlagille syndrome (ALGS), also known as arteriohepatic dysplasia, is a multisystem disorder due to defects in components of the Notch signalling pathway, most commonly due to mutation in JAG1 (ALGS type 1), but in a small proportion of cases mutation in NOTCH2 (ALGS type 2). The main clinical and pathological features are chronic cholestasis due to paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis, minor vertebral segmentation anomalies, characteristic facies, posterior embryotoxon/anterior segment abnormalities, pigmentary retinopathy, and dysplastic kidneys. It follows autosomal dominant inheritance, but reduced penetrance and variable expression are common in this disorder, and somatic/germline mosaicism may also be relatively frequent. This review discusses the clinical features of ALGS, including long-term complications, the clinical and molecular diagnosis, and management.

• Early-onset, severe lipoatrophy in a patient with permanent neonatal diabetes mellitus secondary to a recessive mutation in the INS gene.

  Authors: Marianna Rachmiel, Oscar Rubio-Cabezas, Sian Ellard, Andrew T Hattersley, Kusiel Perlman

  Pediatric diabetes. 09/2011;

  Rachmiel M, Rubio-Cabezas O, Ellard S, Hattersley AT, Perlman K. Early-onset, severe lipoatrophy in a patient with permanent neonatal diabetes mellitus secondary to a recessive mutation in the INSRachmiel M, Rubio-Cabezas O, Ellard S, Hattersley AT, Perlman K. Early-onset, severe lipoatrophy in a patient with permanent neonatal diabetes mellitus secondary to a recessive mutation in the INS gene. We describe a case of neonatal diabetes due to a homozygous mutation (c.3 G>T) at the INS gene, leading to lack of insulin expression and severe hyperglycemia from day one of life requiring permanent insulin replacement therapy. The genetic loss of endogenous insulin production likely led to lack of immune tolerance to insulin, with resultant autoantibody production against exogenous insulin and progressive immune-mediated lipoatrophy at injection sites.

• Congenital hyperinsulinism caused by mutations in ABCC8 (SUR1) gene.

  Authors: Seema Thakur, Sarah E Flanagan, Sian Ellard, I C Verma

  Indian pediatrics. 09/2011; 48(9):733-4.

  Congenital hyperinsulinism is the most frequent cause of severe, persistent hypoglycemia in infancy and childhood. We report a 2.5 year old girl with severe congenital hyperinsulinism. MutationCongenital hyperinsulinism is the most frequent cause of severe, persistent hypoglycemia in infancy and childhood. We report a 2.5 year old girl with severe congenital hyperinsulinism. Mutation analysis showed that the child is a compound heterozygote for two missense mutations in the ABCC8 gene.

• Congenital hyperinsulinism: marked clinical heterogeneity in siblings with identical mutations in the ABCC8 gene.

  Authors: Ritika R Kapoor, Sarah E Flanagan, Sian Ellard, Khalid Hussain

  Clinical endocrinology. 08/2011; 76(2):312-3.

  Congenital Hyperinsulinism (CHI) is a clinically and genetically heterogeneous disease. The clinical heterogeneity may range from mild subtle hypoglycaemia to severe life threatening hypoglycaemia.Congenital Hyperinsulinism (CHI) is a clinically and genetically heterogeneous disease. The clinical heterogeneity may range from mild subtle hypoglycaemia to severe life threatening hypoglycaemia. The commonest genetic cause of congenital hyperinsulinism are mutations in the genes ABCC8 and KCNJ11 encoding the two subunits (SUR1 and Kir6.2 respectively) of the pancreatic β-cell K(ATP) channel. In the Ashkenazi Jewish population two founder mutations in the ABCC8 gene account for about 88% cases of CHI, with the splicing (c.3992-9G>A) mutation being the most prevalent. We report a family with marked intrafamilial clinical variation in four haploidentical siblings who have the same homozygous c.3992-9G>A mutation in the ABCC8 gene. This clinical heterogeneity ranged from having no symptoms of hypoglycaemia to having macrosomia, transient hyperinsulinism to severe hyperinsulinism and then gradual improvement over time followed by development of diabetes mellitus. It is unclear how the same mutation causes such marked clinical heterogeneity. It is possible that the clinical expression may be modified by background genetic factors and other unknown factors involved in regulating gene expression.

• Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease.

  Authors: Michael N Weedon, Robert Hastings, Richard Caswell, Weijia Xie, Konrad Paszkiewicz, Thalia Antoniadi, Maggie Williams, Cath King, Lynn Greenhalgh, Ruth Newbury-Ecob, Sian Ellard

  American journal of human genetics. 08/2011; 89(2):308-12.

  Charcot-Marie-Tooth disease is characterized by length-dependent axonal degeneration with distal sensory loss and weakness, deep-tendon-reflex abnormalities, and skeletal deformities. It is caused byCharcot-Marie-Tooth disease is characterized by length-dependent axonal degeneration with distal sensory loss and weakness, deep-tendon-reflex abnormalities, and skeletal deformities. It is caused by mutations in more than 40 genes. We investigated a four-generation family with 23 members affected by the axonal form (type 2), for which the common causes had been excluded by Sanger sequencing. Exome sequencing of three affected individuals separated by eight meioses identified a single shared novel heterozygous variant, c.917A>G, in DYNC1H1, which encodes the cytoplasmic dynein heavy chain 1 (here, novel refers to a variant that has not been seen in dbSNP131or the August 2010 release of the 1000 Genomes project). Testing of six additional affected family members showed cosegregation and a maximum LOD score of 3.6. The shared DYNC1H1 gene variant is a missense substitution, p.His306Arg, at a highly conserved residue within the homodimerization domain. Three mouse models with different mutations within this domain have previously been reported with age-related progressive loss of muscle bulk and locomotor ability. Cytoplasmic dynein is a large multisubunit motor protein complex and has a key role in retrograde axonal transport in neurons. Our results highlight the importance of dynein and retrograde axonal transport in neuronal function in humans.

• High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes.

  Authors: Tim J McDonald, Beverley M Shields, Jane Lawry, Katharine R Owen, Anna L Gloyn, Sian Ellard, Andrew T Hattersley

  Diabetes care. 06/2011; 34(8):1860-2.

  Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α (HNF1A) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown thatMaturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α (HNF1A) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes. hs-CRP levels were assessed in 750 patients (220 HNF1A, 245 GCK, 54 HNF4-α [HNF4A], 21 HNF1-β (HNF1B), 53 type 1 diabetes, and 157 type 2 diabetes). hs-CRP was lower in HNF1A-MODY (median [IQR] 0.3 [0.1-0.6] mg/L) than type 2 diabetes (1.40 [0.60-3.45] mg/L; P < 0.001) and type 1 diabetes (1.10 [0.50-1.85] mg/L; P < 0.001), HNF4A-MODY (1.45 [0.46-2.88] mg/L; P < 0.001), GCK-MODY (0.60 [0.30-1.80] mg/L; P < 0.001), and HNF1B-MODY (0.60 [0.10-2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP <0.75 mg/L showing 79% sensitivity and 70% specificity (receiver operating characteristic area under the curve = 0.84). hs-CRP levels are lower in HNF1A-MODY than other forms of diabetes and may be used as a biomarker to select patients for diagnostic HNF1A genetic testing.

• Mutations of the same conserved glutamate residue in NBD2 of the sulfonylurea receptor 1 subunit of the KATP channel can result in either hyperinsulinism or neonatal diabetes.

  Authors: Roope Männikkö, Sarah E Flanagan, Xiuli Sim, David Segal, Khalid Hussain, Sian Ellard, Andrew T Hattersley, Frances M Ashcroft

  Diabetes. 06/2011; 60(6):1813-22.

  Two novel mutations (E1506D, E1506G) in the nucleotide-binding domain 2 (NBD2) of the ATP-sensitive K(+) channel (K(ATP) channel) sulfonylurea receptor 1 (SUR1) subunit were detected heterozygouslyTwo novel mutations (E1506D, E1506G) in the nucleotide-binding domain 2 (NBD2) of the ATP-sensitive K(+) channel (K(ATP) channel) sulfonylurea receptor 1 (SUR1) subunit were detected heterozygously in patients with neonatal diabetes. A mutation at the same residue (E1506K) was previously shown to cause congenital hyperinsulinemia. We sought to understand why mutations at the same residue can cause either neonatal diabetes or hyperinsulinemia. Neonatal diabetic patients were sequenced for mutations in ABCC8 (SUR1) and KCNJ11 (Kir6.2). Wild-type and mutant K(ATP) channels were expressed in Xenopus laevis oocytes and studied with electrophysiological methods. Oocytes expressing neonatal diabetes mutant channels had larger resting whole-cell K(ATP) currents than wild-type, consistent with the patients' diabetes. Conversely, no E1506K currents were recorded at rest or after metabolic inhibition, as expected for a mutation causing hyperinsulinemia. K(ATP) channels are activated by Mg-nucleotides (via SUR1) and blocked by ATP (via Kir6.2). All mutations decreased channel activation by MgADP but had little effect on MgATP activation, as assessed using an ATP-insensitive Kir6.2 subunit. Importantly, using wild-type Kir6.2, a 30-s preconditioning exposure to physiological MgATP concentrations (>300 µmol/L) caused a marked reduction in the ATP sensitivity of neonatal diabetic channels, a small decrease in that of wild-type channels, and no change for E1506K channels. This difference in MgATP inhibition may explain the difference in resting whole-cell currents found for the neonatal diabetes and hyperinsulinemia mutations. Mutations in the same residue can cause either hyperinsulinemia or neonatal diabetes. Differentially altered nucleotide regulation by NBD2 of SUR1 can explain the respective clinical phenotypes.

• A conserved tryptophan at the membrane-water interface acts as a gatekeeper for Kir6.2/SUR1 channels and causes neonatal diabetes when mutated.

  Authors: Roope Männikkö, Phillip J Stansfeld, Alexandra S Ashcroft, Andrew T Hattersley, Mark S P Sansom, Sian Ellard, Frances M Ashcroft

  The Journal of physiology. 05/2011; 589(Pt 13):3071-83.

  We identified a novel heterozygous mutation, W68R, in the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, in a patient with transient neonatal diabetes. This tryptophan is absolutelyWe identified a novel heterozygous mutation, W68R, in the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, in a patient with transient neonatal diabetes. This tryptophan is absolutely conserved in mammalian Kir channels. The functional effects of mutations at residue 68 of Kir6.2 were studied by heterologous expression in Xenopus oocytes, and by homology modelling. We found the Kir6.2-W68R mutation causes a small reduction in ATP inhibition in the heterozygous state and an increase in the whole-cell KATP current. This can explain the clinical phenotype of the patient. The effect of the mutation was not charge or size dependent, the order of potency for ATP inhibition being W<M∼L<R∼E∼K∼A<C∼F<Y. Replacement with tyrosine (Y) rendered the KATP channel almost completely insensitive to ATP block, dramatically increased the channel open probability, and affected the interaction of Kir6.2 with SUR1. In different Kir crystal structures the residue corresponding to W68 adopts two distinct positions. In one state, the tryptophan lies in a position that would impede movement of transmembrane domain 2 (TM2) and opening of the gate. In the other state, it is flipped out, enabling movement of TM2. We therefore hypothesise that W68 may act as a molecular'gatekeeper' for Kir channels.

• Persistently autoantibody negative (PAN) type 1 diabetes mellitus in children.

  Authors: Shihab Hameed, Sian Ellard, Helen J Woodhead, Kristen A Neville, Jan L Walker, Maria E Craig, Taylor Armstrong, Liping Yu, George S Eisenbarth, Andrew T Hattersley, Charles F Verge

  Pediatric diabetes. 05/2011; 12(3 Pt 1):142-9.

  Autoantibody-negative children diagnosed with type 1 diabetes might have unrecognized monogenic or type 2 diabetes. At diagnosis of type 1 diabetes (between ages 0.5 and 16.3 yr, n = 470),Autoantibody-negative children diagnosed with type 1 diabetes might have unrecognized monogenic or type 2 diabetes. At diagnosis of type 1 diabetes (between ages 0.5 and 16.3 yr, n = 470), autoantibodies [glutamic acid decarboxylase (GAD), insulinoma-associated protein 2 (IA2), insulin autoantibodies (IAA), and/or islet cell antibody (ICA)] were positive (ab+) in 330 and negative in 37 (unknown in 103). Autoantibody-negative patients were retested at median diabetes duration of 3.2 yr (range 0.9-16.2) for autoantibodies (GAD, IA2, ZnT8), human leukocyte antigen (HLA) typing, non-fasting C-peptide, and sequencing of HNF4A, HNF1A, KCNJ11, and INS. Nineteen (5% of 367) remained persistently autoantibody negative (PAN), 17 were positive on repeat testing (PORT), and 1 refused retesting. No mutations were found in PORT. One PAN was heterozygous for P112L mutation in HNF1A and transferred from insulin to oral gliclazide. Another PAN transferred to metformin and the diagnosis was revised to type 2 diabetes. The remaining 17 PAN were indistinguishable from the ab+ group by clinical characteristics. HLA genotype was at high risk for type 1 diabetes in 82% of remaining PAN and 100% of PORT. After excluding patients with diabetes duration <1 yr, C-peptide was detectable more frequently in the remaining PAN (7/16) and PORT (6/17) than in a random selection of ab+ (3/28, p = 0.03). Conclusions: The diagnosis of type 1 diabetes should be reevaluated in PAN patients, because a subset has monogenic or type 2 diabetes. The remaining PAN have relatively preserved C-peptide compared with ab+, suggesting slower β-cell destruction, but a very high frequency of diabetogenic HLA, implying that type 1B (idiopathic) diabetes is rare.

• KCNJ11 activating mutations cause both transient and permanent neonatal diabetes mellitus in Cypriot patients.

  Authors: Yiannis S Ioannou, Sian Ellard, Andrew Hattersley, Nicos Skordis

  Pediatric diabetes. 03/2011; 12(2):133-7.

  Heterozygous mutations of the KCNJ11 gene encoding the Kir6.2 subunit of the ATP-sensitive potassium channel (K(ATP) channel) of the pancreatic β-cell cause diabetes in about 30-60% of all permanentHeterozygous mutations of the KCNJ11 gene encoding the Kir6.2 subunit of the ATP-sensitive potassium channel (K(ATP) channel) of the pancreatic β-cell cause diabetes in about 30-60% of all permanent neonatal diabetes mellitus cases diagnosed before 6 months of age. The K(ATP) channel plays an essential role in the regulation of the electrical status of the membrane through which the secretion of insulin is activated. Transient neonatal diabetes mellitus due to KCNJ11 mutations is less frequent than abnormalities affecting the imprinted region of chromosome 6q24. We studied the genetic basis of two Cypriot patients who developed diabetes before 6 months of age. They both carried mutations of the KCNJ11 gene. The R201H mutation was identified in a patient who developed hyperglycemia and ketoacidosis at the age of 40 d and was successfully transferred to sulphonylureas which activate the channel through an ATP independent route. The R50Q mutation was identified in a child diagnosed at day 45 after birth with remission of his diabetes at 9 months of age. The same defect was identified both in his asymptomatic mother and the recently diagnosed 'type 2' diabetic maternal grandmother. The remission-relapse mechanism in cases of transient neonatal diabetes is not known. Nevertheless, it is possible that the residue of the mutation within the Kir6.2 molecule is associated with the sensitivity to ATP reflecting to the severity of the diabetic phenotype.