Recessively Inherited<i>LRBA</i>Mutations Cause Autoimmunity Presenting as Neonatal Diabetes

Johnson, Matthew; Allen, Hana Lango; Senani, Aisha Al; Elbarbary, Nancy Samir; Şıklar, Zeynep; Berberoğlu, Merih; Imane, Z.; Haghighi, Alireza; Razavi, Zahra; Ullah, Irfan; Al-Yaarubi, Saif; Gardner, Daphne Su‐Lyn; Ellard, Sian; Hattersley, Andrew T.; Flanagan, Sarah E.

doi:10.2337/db17-0040

Cited by 58 publications

(28 citation statements)

References 28 publications

(56 reference statements)

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“…88 The disease-causing LRBA mutation was identified during genetic screening of patients with combined variable immunodeficiency, 92 IPEX syndrome-like disease, 91 and neonatal T1D. 93 Immunologically, patients had normal or reduced lymphocyte counts, mostly normal T-cell levels with reduced Treg cell counts, normal or low total B-cell counts with a reduced memory compartment, 89,92 and increased numbers of circulating follicular helper T cells. 91,94 Infections, especially in the lung, were common and caused by various bacterial, viral, and fungal microorganisms.…”

Section: Monogenic Diseases That Affect Foxp3 1 Treg Cell Function: Cmentioning

confidence: 99%

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

Cepika

Sato

Liu

et al. 2018

Journal of Allergy and Clinical Immunology

104

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Section: Monogenic Diseases That Affect Foxp3 1 Treg Cell Function: Cmentioning

confidence: 99%

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

Cepika

Sato

Liu

et al. 2018

Journal of Allergy and Clinical Immunology

104

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“…PNDM is a genetically heterogeneous disorder due to mutations in 23 different genes described to date: KCNJ11 , ABCC8 , FOXP3 , GCK , PDX1 , pancreas-specific transcription factor 1A (PTF1A) , EIF2AK3 , SLC2A2 , GATA6 , GATA4 , SLC19A2 , WFS1 , NEUROD1 , NEUROG3 , RFX6 , LRBA , NKX2-2 , MNX1 , IER3IP1 , INS , STAT3 , GLIS3 and HNF1B ( 3 , 4 , 5 , 6 , 7 , 8 , 9 ). These mutations can either compromise insulin secretion, disturb pancreas or islet cell development or result in autoimmune destruction of the beta cells.…”

Section: Introductionmentioning

confidence: 99%

Neonatal Diabetes: Two Cases with Isolated Pancreas Agenesis due to Homozygous PTF1A Enhancer Mutations and One with Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome due to KCNJ11 Mutation

Evliyaoğlu

Ercan

Ataoğlu³

et al. 2018

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Neonatal diabetes mellitus is a rare form of monogenic diabetes which is diagnosed in the first six months of life. Here we report three patients with neonatal diabetes; two with isolated pancreas agenesis due to mutations in the pancreas-specific transcription factor 1A (PTF1A) enhancer and one with developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, due to a KCNJ11 mutation. The two cases with mutations in the distal enhancer of PTF1A had a homozygous g.23508363A>G and a homozygous g.23508437A>G mutation respectively. Previous functional analyses showed that these mutations can decrease expression of PTF1A which is involved in pancreas development. Both patients were born small for gestational age to consanguineous parents. Both were treated with insulin and pancreatic enzymes. One of these patients’ fathers was also homozygous for the PTF1A mutation, whilst his partner and the parents of the other patient were heterozygous carriers. In the case with DEND sydrome, a previosly reported heterozygous KCNJ11 mutation, p.Cys166Tyr (c.497G>A), was identified. This patient was born to nonconsanguineous parents with normal birth weight. The majority of neonatal diabetes patients with KCNJ11 mutations will respond to sulphonylurea treatment. Therefore Glibenclamide, an oral antidiabetic of the sulphonylurea group, was started. This treatment regimen relatively improved blood glucose levels and neurological symptoms in the short term. Because we could not follow the patient in the long term, we are not able to draw conclusions about the efficacy of the treatment. Although neonatal diabetes mellitus can be diagnosed clinically, genetic analysis is important since it is a guide for the treatment and for prognosis.

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“…A mutation in a known monogenic autoimmunity gene was identified in 47% (37/79) of the individuals with diabetes and ≥1 autoimmune disorder diagnosed before the age of 5 years; 25 male participants had a hemizygous mutation in FOXP3 , eight individuals had recessively inherited mutations in LRBA , two had recessively inherited IL2RA mutations and two had heterozygous gain-of-function STAT3 mutations. Twelve of these individuals have been reported previously [ 2 , 3 , 15 ]. The remaining 42 individuals had early-onset multiple autoimmunity but did not have a mutation in a known gene.…”

Section: Resultsmentioning

confidence: 99%

“…For example, hemizygous mutations in FOXP3 cause immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, which presents in the neonatal period with diabetes, protein-losing enteropathy and severe eczema [ 1 ]. Similarly, individuals with infantile-onset multisystem autoimmune disease due to dominant gain-of-function STAT3 mutations or common variable immunodeficiency 8 with autoimmunity due to recessively inherited LRBA mutations may present with neonatal diabetes [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

A type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early-onset clustering of polygenic autoimmunity with diabetes

et al. 2018

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Aims/hypothesis Identifying individuals suitable for monogenic autoimmunity testing and gene discovery studies is challenging: early-onset type 1 diabetes mellitus can cluster with additional autoimmune diseases due to shared polygenic risk and islet-and other organ-specific autoantibodies are present in both monogenic and polygenic aetiologies. We aimed to assess whether a type 1 diabetes genetic risk score (GRS) could identify monogenic autoimmune diabetes and be useful to prioritise individuals for gene discovery studies.Methods We studied 79 individuals with diabetes and at least one additional autoimmune disease diagnosed before the age of 5 years. We screened all participants for the seven genes known to cause monogenic autoimmunity that can include diabetes (AIRE, IL2RA, FOXP3, LRBA, STAT1, STAT3, STAT5B). We genotyped the top ten risk alleles for type 1 diabetes, including HLA and non-HLA loci, to generate a type 1 diabetes GRS. Results Of the 79 individuals studied, 37 (47%) had mutations in the monogenic autoimmunity genes. The type 1 diabetes GRS was lower in these individuals than in those without mutations in these genes (median 9th vs 49th centile of type 1 diabetes controls, p < 0.0001). Age of diabetes diagnosis and type 1 diabetes GRS combined to be highly discriminatory of monogenic autoimmunity (receiver operating characteristic AUC: 0.88). Most individuals without a mutation in a known gene had a high type 1 diabetes GRS, suggesting that they have polygenic clustering of type 1 diabetes and additional autoimmunity and should not be included in gene discovery studies. Conclusions/interpretationWe have shown that the type 1 diabetes GRS can identify individuals likely to have monogenic autoimmunity, helping both diagnostic testing and novel monogenic autoimmunity gene discovery. Individuals with monogenic autoimmunity have a different clinical course to those with polygenic type 1 diabetes and can respond well to therapies targeting the underlying genetic defect.

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Recessively InheritedLRBAMutations Cause Autoimmunity Presenting as Neonatal Diabetes

Cited by 58 publications

References 28 publications

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

Neonatal Diabetes: Two Cases with Isolated Pancreas Agenesis due to Homozygous PTF1A Enhancer Mutations and One with Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome due to KCNJ11 Mutation

A type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early-onset clustering of polygenic autoimmunity with diabetes

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