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1.  GATA6 Mutations Cause a Broad Phenotypic Spectrum of Diabetes From Pancreatic Agenesis to Adult-Onset Diabetes Without Exocrine Insufficiency 
Diabetes  2013;62(3):993-997.
We recently reported de novo GATA6 mutations as the most common cause of pancreatic agenesis, accounting for 15 of 27 (56%) patients with insulin-treated neonatal diabetes and exocrine pancreatic insufficiency requiring enzyme replacement therapy. We investigated the role of GATA6 mutations in 171 subjects with neonatal diabetes of unknown genetic etiology from a cohort of 795 patients with neonatal diabetes. Mutations in known genes had been confirmed in 624 patients (including 15 GATA6 mutations). Sequencing of the remaining 171 patients identified nine new case subjects (24 of 795, 3%). Pancreatic agenesis was present in 21 case subjects (six new); two patients had permanent neonatal diabetes with no enzyme supplementation and one had transient neonatal diabetes. Four parents with heterozygous GATA6 mutations were diagnosed with diabetes outside the neonatal period (12–46 years). Subclinical exocrine insufficiency was demonstrated by low fecal elastase in three of four diabetic patients who did not receive enzyme supplementation. One parent with a mosaic mutation was not diabetic but had a heart malformation. Extrapancreatic features were observed in all 24 probands and three parents, with congenital heart defects most frequent (83%). Heterozygous GATA6 mutations cause a wide spectrum of diabetes manifestations, ranging from pancreatic agenesis to adult-onset diabetes with subclinical or no exocrine insufficiency.
PMCID: PMC3581234  PMID: 23223019
2.  The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype 
Journal of Medical Genetics  2013;51(3):165-169.
Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined.
Methods and Results
We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known.
The HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype.
PMCID: PMC3932761  PMID: 24285859
Renal Medicine; Calcium and Bone; Clinical Genetics; Diabetes; Metabolic Disorders
4.  An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy 
Nature genetics  2013;45(8):947-950.
DNA polymerase delta, whose catalytic subunit is encoded by POLD1, is responsible for lagging strand DNA synthesis during DNA replication1. It achieves this with high fidelity due to its intrinsic 3′ to 5′ exonuclease activity, which confers proofreading ability. Missense mutations in the exonuclease domain of POLD1 have recently been shown to predispose to colorectal and endometrial cancer2. Here we report a recurring heterozygous single amino acid deletion at the polymerase active site of POLD1 that abolishes DNA polymerase activity but only mildly impairs 3′ to 5′ exonuclease activity. This mutation causes a distinct multisystem disorder that includes subcutaneous lipodystrophy, deafness, mandibular hypoplasia and hypogonadism in males. This suggests that perturbation of function of the ubiquitously expressed POLD1 polymerase has surprisingly tissue-specific effects in man, and argues for an important role for POLD1 function in adipose tissue homeostasis.
PMCID: PMC3785143  PMID: 23770608
5.  Analysis of Transcription Factors Key for Mouse Pancreatic Development Establishes NKX2-2 and MNX1 Mutations as Causes of Neonatal Diabetes in Man 
Cell Metabolism  2014;19(1):146-154.
Understanding transcriptional regulation of pancreatic development is required to advance current efforts in developing beta cell replacement therapies for patients with diabetes. Current knowledge of key transcriptional regulators has predominantly come from mouse studies, with rare, naturally occurring mutations establishing their relevance in man. This study used a combination of homozygosity analysis and Sanger sequencing in 37 consanguineous patients with permanent neonatal diabetes to search for homozygous mutations in 29 transcription factor genes important for murine pancreatic development. We identified homozygous mutations in 7 different genes in 11 unrelated patients and show that NKX2-2 and MNX1 are etiological genes for neonatal diabetes, thus confirming their key role in development of the human pancreas. The similar phenotype of the patients with recessive mutations and mice with inactivation of a transcription factor gene support there being common steps critical for pancreatic development and validate the use of rodent models for beta cell development.
Graphical Abstract
•Homozygous mutations in seven pancreatic transcription factors cause neonatal diabetes•Homozygous NKX2-2 and MNX1 mutations were found in five patients•Confirms NKX2-2 and MNX1 are critical for murine and human pancreas development•Similar phenotypes in mouse and man validate models for beta cell development
Analyzing a large collection of consanguineous patients with permanent neonatal diabetes, Flanagan et al. performed a comprehensive search for recessive mutations in transcription factors known to be critical for mouse pancreatic development. They identify seven pancreatic transcription factors that cause neonatal diabetes, including NKX2-2 and MNX1.
PMCID: PMC3887257  PMID: 24411943
6.  tRNA Methyltransferase Homolog Gene TRMT10A Mutation in Young Onset Diabetes and Primary Microcephaly in Humans 
PLoS Genetics  2013;9(10):e1003888.
We describe a new syndrome of young onset diabetes, short stature and microcephaly with intellectual disability in a large consanguineous family with three affected children. Linkage analysis and whole exome sequencing were used to identify the causal nonsense mutation, which changed an arginine codon into a stop at position 127 of the tRNA methyltransferase homolog gene TRMT10A (also called RG9MTD2). TRMT10A mRNA and protein were absent in lymphoblasts from the affected siblings. TRMT10A is ubiquitously expressed but enriched in brain and pancreatic islets, consistent with the tissues affected in this syndrome. In situ hybridization studies showed that TRMT10A is expressed in human embryonic and fetal brain. TRMT10A is the mammalian ortholog of S. cerevisiae TRM10, previously shown to catalyze the methylation of guanine 9 (m1G9) in several tRNAs. Consistent with this putative function, in silico topology prediction indicated that TRMT10A has predominant nuclear localization, which we experimentally confirmed by immunofluorescence and confocal microscopy. TRMT10A localizes to the nucleolus of β- and non-β-cells, where tRNA modifications occur. TRMT10A silencing induces rat and human β-cell apoptosis. Taken together, we propose that TRMT10A deficiency negatively affects β-cell mass and the pool of neurons in the developing brain. This is the first study describing the impact of TRMT10A deficiency in mammals, highlighting a role in the pathogenesis of microcephaly and early onset diabetes. In light of the recent report that the type 2 diabetes candidate gene CDKAL1 is a tRNA methylthiotransferase, the findings in this family suggest broader relevance of tRNA methyltransferases in the pathogenesis of type 2 diabetes.
Author Summary
The inherited predisposition to type 2 diabetes is attributed to common variants in over 60 loci. Among these risk variants is CDKAL1, which has recently been shown to be a tRNA modifying enzyme (methylthiotransferase). Genetic variants of different severity can generate a spectrum of monogenic and polygenic forms of diabetes. Here we describe a new syndrome of young onset diabetes, short stature and microcephaly (small brain size) with intellectual disability in a large consanguineous family. By linkage analysis and whole exome sequencing we identified a nonsense mutation in TRMT10A, a gene that has hitherto not been studied in mammals. The yeast homolog TRM10 has been shown to be a tRNA modifying enzyme with methyltransferase activity. We demonstrate that TRMT10A mRNA and protein are absent in cells from the affected siblings. TRMT10A localizes to the nucleolus, where tRNA modifications occur. TRMT10A silencing induces cell death in insulin-producing pancreatic β-cells, suggesting that TRMT10A deficiency may reduce β-cell mass and the pool of neurons in the brain. This is the first study describing the impact of TRMT10A deficiency in man. Our findings may have broader relevance for the understanding of the pathogenesis of type 2 diabetes and microcephaly.
PMCID: PMC3814312  PMID: 24204302
7.  Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia 
Diabetologia  2013;57:54-56.
Heterozygous glucokinase (GCK) mutations cause mild, fasting hyperglycaemia from birth. Although patients are usually asymptomatic and have glycaemia within target ranges, some are put on pharmacological treatment. We aimed to investigate how many patients are on pharmacological treatment and the impact of treatment on glycaemic control.
Treatment details were ascertained for 799 patients with heterozygous GCK mutations. In a separate, longitudinal study, HbA1c was obtained for 16 consecutive patients receiving insulin (n = 10) or oral hypoglycaemic agents (OHAs) (n = 6) whilst on treatment, and again having discontinued treatment following a genetic diagnosis of GCK-MODY. For comparison, HbA1c before and after genetic testing was studied in a control group (n = 18) not receiving pharmacological therapy.
At referral for genetic testing, 168/799 (21%) of patients were on pharmacological treatment (13.5% OHAs, 7.5% insulin). There was no difference in the HbA1c of these patients compared with those receiving no treatment(median [IQR]: 48 [43, 51] vs 46 [43, 50] mmol/mol, respectively; 6.5% [6.1%, 6.8%] vs 6.4% [6.1%, 6.7%]; p = 0.11). Following discontinuation of pharmacological treatment in 16 patients, HbA1c did not change. The mean change in HbA1c was −0.68 mmol/mol (95% CI: −2.97, 1.61) (−0.06% [95% CI: −0.27, 0.15]).
Prior to a genetic diagnosis, 21% of patients were on pharmacological treatment. HbA1c was no higher than in untreated patients and did not change when therapy was discontinued, suggesting no impact on glycaemia. The lack of response to pharmacological therapy is likely to reflect the regulated hyperglycaemia seen in these patients owing to their glucose sensing defect and is an example of pharmacogenetics.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-3075-x) contains peer reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3855531  PMID: 24092492
GCK mutation; Glucokinase; MODY; Pharmacogenetics; Treatment
10.  Diabetes Mellitus in Neonates and Infants: Genetic Heterogeneity, Clinical Approach to Diagnosis, and Therapeutic Options 
Hormone Research in Pædiatrics  2013;80(3):137-146.
Over the last decade, we have witnessed major advances in the understanding of the molecular basis of neonatal and infancy-onset diabetes. It is now widely accepted that diabetes presenting before 6 months of age is unlikely to be autoimmune type 1 diabetes. The vast majority of such patients will have a monogenic disorder responsible for the disease and, in some of them, also for a number of other associated extrapancreatic clinical features. Reaching a molecular diagnosis will have immediate clinical consequences for about half of affected patients, as identification of a mutation in either of the two genes encoding the ATP-sensitive potassium channel allows switching from insulin injections to oral sulphonylureas. It also facilitates genetic counselling within the affected families and predicts clinical prognosis. Importantly, monogenic diabetes seems not to be limited to the first 6 months but extends to some extent into the second half of the first year of life, when type 1 diabetes is the more common cause of diabetes. From a scientific perspective, the identification of novel genetic aetiologies has provided important new knowledge regarding the development and function of the human pancreas.
PMCID: PMC3884170  PMID: 24051999
Neonatal diabetes; Monogenic diabetes of infancy ; Permanent neonatal diabetes; Transient neonatal diabetes ; Type 1 diabetes

11.  Multiple type 2 diabetes susceptibility genes following genome-wide association scan in UK samples 
Science (New York, N.Y.)  2007;316(5829):1336-1341.
The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1,924 diabetic cases and 2,938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3,757 additional cases and 5,346 controls, and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insights into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.
PMCID: PMC3772310  PMID: 17463249
12.  Antenatal Diagnosis of Fetal Genotype Determines if Maternal Hyperglycemia Due to a Glucokinase Mutation Requires Treatment 
Diabetes Care  2012;35(9):1832-1834.
In women with hyperglycemia due to heterozygous glucokinase (GCK) mutations, the fetal genotype determines its growth. If the fetus inherits the mutation, birth weight is normal when maternal hyperglycemia is not treated, whereas intensive treatment may adversely reduce fetal growth. However, fetal genotype is not usually known antenatally, making treatment decisions difficult.
We report two women with gestational diabetes mellitus resulting from GCK mutations with hyperglycemia sufficient to merit treatment.
In both women, DNA from chorionic villus sampling, performed after high-risk aneuploidy screening, showed the fetus had inherited the GCK mutation. Therefore, maternal hyperglycemia was not treated. Both offspring had a normal birth weight and no peripartum complications.
In pregnancies where the mother has hyperglycemia due to a GCK mutation, knowing the fetal GCK genotype guides the management of maternal hyperglycemia. Fetal genotyping should be performed when fetal DNA is available from invasive prenatal diagnostic testing.
PMCID: PMC3425005  PMID: 22773699
13.  Insights Into the Pathogenicity of Rare Missense GCK Variants From the Identification and Functional Characterization of Compound Heterozygous and Double Mutations Inherited in Cis 
Diabetes Care  2012;35(7):1482-1484.
To demonstrate the importance of using a combined genetic and functional approach to correctly interpret a genetic test for monogenic diabetes.
We identified three probands with a phenotype consistent with maturity-onset diabetes of the young (MODY) subtype GCK-MODY, in whom two potential pathogenic mutations were identified: [R43H/G68D], [E248 K/I225M], or [G261R/D217N]. Allele-specific PCR and cosegregation were used to determine phase. Single and double mutations were kinetically characterized.
The mutations occurred in cis (double mutants) in two probands and in trans in one proband. Functional studies of all double mutants revealed inactivating kinetics. The previously reported GCK-MODY mutations R43H and G68D were inherited from an affected father and unaffected mother, respectively. Both our functional and genetic studies support R43H as the cause of GCK-MODY and G68D as a neutral rare variant.
These data highlight the need for family/functional studies, even for previously reported pathogenic mutations.
PMCID: PMC3379612  PMID: 22611063
14.  Use of HbA1c in the Identification of Patients with Hyperglycaemia Caused by a Glucokinase Mutation: Observational Case Control Studies 
PLoS ONE  2013;8(6):e65326.
HaemoglobinA1c (HbA1c) is recommended for diabetes diagnosis but fasting plasma glucose (FPG) has been useful for identifying patients with glucokinase (GCK) mutations which cause lifelong persistent fasting hyperglycaemia. We aimed to derive age-related HbA1c reference ranges for these patients to determine how well HbA1c can discriminate patients with a GCK mutation from unaffected family members and young-onset type 1 (T1D) and type 2 diabetes (T2D) and to investigate the proportion of GCK mutation carriers diagnosed with diabetes using HbA1c and/or FPG diagnostic criteria.
Individuals with inactivating GCK mutations (n = 129), familial controls (n = 100), T1D (n = 278) and T2D (n = 319) aged ≥18years were recruited. Receiver Operating Characteristic (ROC) analysis determined effectiveness of HbA1c and FPG to discriminate between groups.
HbA1c reference ranges in subjects with GCK mutations were: 38–56 mmol/mol (5.6–7.3%) if aged ≤40years; 41–60 mmol/mol (5.9–7.6%) if >40years. All patients (123/123) with a GCK mutation were above the lower limit of the HbA1c age-appropriate reference ranges. 69% (31/99) of controls were below these lower limits. HbA1c was also effective in discriminating those with a GCK mutation from those with T1D/T2D. Using the upper limit of the age-appropriate reference ranges to discriminate those with a mutation from those with T1D/T2D correctly identified 97% of subjects with a mutation. The majority (438/597 (73%)) with other types of young-onset diabetes had an HbA1c above the upper limit of the age-appropriate GCK reference range. HbA1c ≥48 mmol/mol classified more people with GCK mutations as having diabetes than FPG ≥7 mmol/l (68% vs. 48%, p = 0.0009).
Current HbA1c diagnostic criteria increase diabetes diagnosis in patients with a GCK mutation. We have derived age-related HbA1c reference ranges that can be used for discriminating hyperglycaemia likely to be caused by a GCK mutation and aid identification of probands and family members for genetic testing.
PMCID: PMC3683003  PMID: 23799006
15.  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 
Diabetes Care  2012;35(6):1206-1212.
Misdiagnosis 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.
Individuals 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 α (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.
In 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 (HbA1c 8.8 vs. 7.3% at 3 months; P = 0.02).
The 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.
PMCID: PMC3357216  PMID: 22432108
16.  Identification of a SLC19A2 nonsense mutation in Persian families with thiamine-responsive megaloblastic anemia 
Gene  2013;519(2):295-297.
Thiamine-responsive megaloblastic anemia (TRMA) is an autosomal recessive syndrome characterized by early-onset anemia, diabetes, and hearing loss caused by mutations in the SLC19A2 gene. We studied the genetic cause and clinical features of this condition in patients from the Persian population. A clinical and molecular investigation was performed in four patients from three families and their healthy family members. All had the typical diagnostic criteria. The onset of hearing loss in three patients was at birth and one patient also had a stroke and seizure disorder. Thiamine treatment effectively corrected the anemia in all of our patients but did not prevent hearing loss. Diabetes was improved in one patient who presented at the age of 8 months with anemia and diabetes after 2 months of starting thiamine. The coding regions of SLC19A2 were sequenced in all patients. The identified mutation was tested in all members of the families. Molecular analyses identified a homozygous nonsense mutation c.697C > T (p.Gln233*) as the cause of the disease in all families. This mutation was previously reported in a Turkish patient with TRMA and is likely to be a founder mutation in the Persian population.
► A non-sense SLC19A2 in four patients with TRMA indicating its high frequency in Persian population. ► Most patients with this mutation had short stature. ► This study expands the knowledge about the of genotype–phenotype correlations in TRMA. ► The results have implications for genetic counseling in other affected families.
PMCID: PMC3725413  PMID: 23454484
TRMA, thiamine-responsive megaloblastic anemia; PCR, polymerase chain reaction; CT scan, computerized tomography scan; MCV, mean corpuscular volume; WBC, white blood cell; SDS, standard deviation score; MPH, mid-parental height; TRMA; Thiamine-responsive megaloblastic anemia; Rogers syndrome; SLC19A2
17.  Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism 
European Journal of Endocrinology  2013;168(4):557-564.
Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) are known to cause CHI.
To characterise the clinical and molecular aspects of a large cohort of patients with CHI.
Three hundred patients were recruited and clinical information was collected before genotyping. ABCC8 and KCNJ11 genes were analysed in all patients. Mutations in GLUD1, HADH, GCK and HNF4A genes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A).
Mutations were identified in 136/300 patients (45.3%). Mutations in ABCC8/KCNJ11 were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in the ABCC8/KCNJ11 genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations in ABCC8/KCNJ11 (n=15), HNF4A (n=7), GLUD1 (n=16) and HADH (n=3).
A genetic diagnosis was made for 45.3% of patients in this large series. Mutations in the ABCC8 gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms.
PMCID: PMC3599069  PMID: 23345197
18.  Alagille syndrome: pathogenesis, diagnosis and management 
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 (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.
PMCID: PMC3283172  PMID: 21934706
Alagille syndrome; arteriohepatic dysplasia; JAG1 gene; NOTCH2 gene; 20p12 deletion
19.  Long-Term Follow-up of a Successfully Treated Case of Congenital Pyridoxine-Dependent Epilepsy 
JIMD Reports  2013;10:103-106.
Autosomal recessive disorders affecting pyridoxine (vitamin B6) metabolism are a rare but well-recognized cause of neonatal seizures. Antiquitin deficiency, caused by mutations in ALDH7A1, is a disorder of the lysine degradation pathway causing accumulation of an intermediate that complexes with pyridoxal phosphate. Reports of long-term follow-up of neonatal pyridoxine-dependent seizures (PDS) remain scarce and prognostic information is varied. We report a case of PDS in a 47-year-old lady who originally presented shortly after birth in 1964. Pyridoxine replacement was successful and diagnostic confirmation was obtained later in life, initially by biochemical analysis of serum pipecolic acid. Subsequently we organized genetic analysis of ALDH7A1, which revealed compound heterozygous mutations. To our knowledge, this represents the longest duration of follow-up published to date.
PMCID: PMC3755577  PMID: 23430810
20.  Identification of a novel nonsense mutation and a missense substitution in the AGPAT2 gene causing congenital generalized lipodystrophy type 1 
Congenital generalized lipodystrophy (CGL) is an autosomal recessive disease characterized by the generalized scant of adipose tissue. CGL type 1 is caused by mutations in gene encoding 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2). A clinical and molecular genetic investigation was performed in affected and unaffected members of two families with CGL type 1. The AGPAT2 coding region was sequenced in index cases of the two families. The presence of the identified mutations in relevant parents was tested. We identified a novel nonsense mutation (c.685G>T, p.Glu229*) and a missense substitution (c.514G>A, p.Glu172Lys). The unaffected parents in both families were heterozygous carrier of the relevant mutation. The results expand genotype–phenotype spectrum in CGL1 and will have applications in prenatal and early diagnosis of the disease. This is the first report of Persian families identified with AGPAT2 mutations.
► First diagnosis of congenital generalized lipodystrophy type 1 in Persian population. ► Molecular analysis identified a novel nonsense mutation and a missense substitution in the AGPAT2. ► The patients did not have diabetes mellitus or hyperinsulinemia. ► The mutations found are candidates for CGL screening. ► The results expand the knowledge about the genotype–phenotype correlations in CGL.
PMCID: PMC3471069  PMID: 22902344
Congenital generalized lipodystrophy; CGL; Berardinelli-Seip syndrome; AGPAT2
21.  High-Sensitivity CRP Discriminates HNF1A-MODY From Other Subtypes of Diabetes 
Diabetes Care  2011;34(8):1860-1862.
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 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.
PMCID: PMC3142017  PMID: 21700917
22.  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 
Diabetes  2011;60(6):1813-1822.
Two novel mutations (E1506D, E1506G) in the nucleotide-binding domain 2 (NBD2) of the ATP-sensitive K+ channel (KATP 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 KATP channels were expressed in Xenopus laevis oocytes and studied with electrophysiological methods.
Oocytes expressing neonatal diabetes mutant channels had larger resting whole-cell KATP 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. KATP 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.
PMCID: PMC3114383  PMID: 21617188
23.  Wolcott-Rallison Syndrome Due to a Novel Mutation (R491X) in EIF2AK3 Gene 
Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disordercharacterized by early-onset diabetes, spondyloepiphyseal dysplasia,tendency to skeletal fractures secondary to osteopenia, and growthretardation. Mutations in the eukaryotic translation initiation factor 2αkinase (EIF2AK3)gene are responsible for this disorder. Here, wedescribe a boy with neonatal diabetes, diagnosed at 2 months of age,who developed severe growth retardation and a skeletal fracture duringthe follow-up period. The patient’s skeletal X-ray revealed findings ofskeletal dysplasia. A clinical diagnosis of WRS was confirmed by theidentification of a novel homozygous nonsense mutation (R491X) in exon9 of the EIF2AK3 gene. The aim of this report is to raise the awarenessfor Wolcott-Rallison syndrome in cases presenting with isolatedneonatal diabetes. This patient demonstrates that the other findings ofthis syndrome might be obscured by a diagnosis of isolated neonataldiabetes.
Conflict of interest:None declared.
PMCID: PMC3386768  PMID: 22672868
Wolcott-Rallison syndrome; neonatal diabetes; Skeletal dysplasia
24.  Leucine-sensitive hyperinsulinaemic hypoglycaemia in patients with loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase 
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 β-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.
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.
Patients demonstrated severe HH (glucose range 1.7–3.2 mmol/l; insulin range 4.8-63.8 mU/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 and half 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.
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).
PMCID: PMC3433310  PMID: 22583614
Hyperinsulinism; Hypoglycaemia; Leucine tolerance
25.  Permanent Neonatal Diabetes and Enteric Anendocrinosis Associated With Biallelic Mutations in NEUROG3 
Diabetes  2011;60(4):1349-1353.
NEUROG3 plays a central role in the development of both pancreatic islets and enteroendocrine cells. Homozygous hypomorphic missense mutations in NEUROG3 have been recently associated with a rare form of congenital malabsorptive diarrhea secondary to enteroendocrine cell dysgenesis. Interestingly, the patients did not develop neonatal diabetes but childhood-onset diabetes. We hypothesized that null mutations in NEUROG3 might be responsible for the disease in a patient with permanent neonatal diabetes and severe congenital malabsorptive diarrhea.
The single coding exon of NEUROG3 was amplified and sequenced from genomic DNA. The mutant protein isoforms were functionally characterized by measuring their ability to bind to an E-box element in the NEUROD1 promoter in vitro and to induce ectopic endocrine cell formation and cell delamination after in ovo chicken endoderm electroporation.
Two different heterozygous point mutations in NEUROG3 were identified in the proband [c.82G>T (p.E28X) and c.404T>C (p.L135P)], each being inherited from an unaffected parent. Both in vitro and in vivo functional studies indicated that the mutant isoforms are biologically inactive. In keeping with this, no enteroendocrine cells were detected in intestinal biopsy samples from the patient.
Severe deficiency of neurogenin 3 causes a rare novel subtype of permanent neonatal diabetes. This finding confirms the essential role of NEUROG3 in islet development and function in humans.
PMCID: PMC3064109  PMID: 21378176

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