scholarly journals A novel splice-site mutation of the HNF1B gene in a family with maturity onset diabetes of the young type 5 (MODY5)

2020 ◽  
Vol 2020 ◽  
Author(s):  
Yuki Fujita ◽  
Daisuke Tanaka ◽  
Hisato Tatsuoka ◽  
Miho Matsubara ◽  
Takanori Hyo ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Splice Site ◽  
Early Onset ◽  
Genetic Diagnosis ◽  
Splice Site Mutation ◽  
Maturity Onset Diabetes ◽  
Site Mutation ◽  
Renal Anomalies ◽  
Onset Diabetes ◽  
Appropriate Treatment

Summary Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes mellitus characterised by early onset and dominant inheritance. Delayed diagnosis or misdiagnosis as type 1 or type 2 diabetes mellitus is common. Definitive genetic diagnosis is essential for appropriate treatment of patients with MODY. The hepatocyte nuclear factor 1-beta (HNF1B) gene is responsible for MODY type 5 (MODY5), which has distinctive clinical features including renal disease. MODY5 should always be considered by clinicians in patients with early onset diabetes and renal anomalies. We report a case of a 30-year-old Japanese male with early-onset diabetes mellitus, renal anomalies and family history of diabetes that was suggestive of MODY5. Renal histology showed no evidence of diabetic nephropathy. Genetic testing revealed a novel heterozygous splice-site mutation of the HNF1B gene in the family members. It was strongly suggested that the mutation could underlie our patient’s MODY5. Learning points: Genetic diagnosis of MODY is relevant for appropriate treatment. Dominantly inherited early-onset diabetes mellitus with renal cysts suggests MODY5. Scanning the non-coding regions is important for not missing a mutation in HNF1B.

scholarly journals NEUROD1 mutation in an Italian patient with maturity onset diabetes of the young 6: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Lucia Brodosi ◽  
Bianca Baracco ◽  
Vilma Mantovani ◽  
Loris Pironi
Keyword(s):  
Diabetes Mellitus ◽  
Beta Cells ◽  
Early Onset ◽  
Genetic Diagnosis ◽  
Glucose Monitoring ◽  
Maturity Onset Diabetes ◽  
Family History Of Diabetes ◽  
Onset Diabetes ◽  
Dominant Disease ◽  
Basal Bolus

Abstract Background Maturity Onset Diabetes of the Young (MODY) is a monogenic, autosomal, dominant disease that results in beta-cells dysfunction with consequent hyperglycaemia. It represents a rare form of diabetes (1–2% of all the cases). Sulphonylureas (SUs) represent the first-line treatment for this form of diabetes mellitus. NEUROD1 is expressed by the nervous and the pancreatic tissues, and it is necessary for the proper development of beta cells. A neurogenic differentiation factor 1 (NEUROD1) gene mutation causes beta-cells dysfunction, inadequate insulin secretion, and hyperglycaemia (MODY 6). Case presentation We have documented a new missense mutation (p.Met114Leu c.340A > C) of the NEUROD1 gene, pathogenetic for diabetes mellitus, in a 48 years-old man affected by diabetes since the age of 25 and treated with insulin basal-bolus therapy. Unfortunately, an attempt to replace rapid insulin with dapagliflozin has failed. However, after the genetic diagnosis of MODY6 and treatment with SUs, he was otherwise able to suspend rapid insulin and close glucose monitoring. Interestingly, our patient had an early onset dilated cardiomyopathy, though no data about cardiac diseases in patients with MODY 6 are available. Conclusions Diagnostic criteria for MODY can overlap with other kinds of diabetes and most cases of genetic diabetes are still misdiagnosed as diabetes type 1 or 2. We encourage to suspect this disease in patients with a strong family history of diabetes, normal BMI, early-onset, and no autoimmunity. The appropriate therapy simplifies disease management and improves the quality of the patient’s life.

Early-onset encephalopathy with epilepsy associated with a novel splice site mutation inSMC1A

2015 ◽  
Vol 167 (12) ◽  
pp. 3076-3081 ◽  
Author(s):  
Nicolas Lebrun ◽  
Sébastien Lebon ◽  
Pierre-Yves Jeannet ◽  
Sébastien Jacquemont ◽  
Pierre Billuart ◽  
...  
Keyword(s):  
Splice Site ◽  
Early Onset ◽  
Splice Site Mutation ◽  
Site Mutation

Mutations of maturity-onset diabetes of the young (MODY) genes in Thais with early-onset type 2 diabetes mellitus

2009 ◽  
Vol 70 (6) ◽  
pp. 847-853 ◽  
Author(s):  
Nattachet Plengvidhya ◽  
Watip Boonyasrisawat ◽  
Nalinee Chongjaroen ◽  
Prapaporn Jungtrakoon ◽  
Sutin Sriussadaporn ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Early Onset ◽  
Maturity Onset Diabetes ◽  
Onset Type ◽  
Onset Diabetes

scholarly journals Mother-to-Child Transmitted WT1 Splice-Site Mutation Is Responsible for Distinct Glomerular Diseases

1999 ◽  
Vol 10 (10) ◽  
pp. 2219-2223
Author(s):  
ERICK DENAMUR ◽  
NATHALIE BOCQUET ◽  
BEATRICE MOUGENOT ◽  
FRANCIS DA SILVA ◽  
LAURENCE MARTINAT ◽  
...  
Keyword(s):  
Splice Site ◽  
Early Onset ◽  
Index Case ◽  
Wilms Tumor ◽  
Splice Site Mutation ◽  
Normal Female ◽  
Diffuse Mesangial Sclerosis ◽  
Frasier Syndrome ◽  
Site Mutation ◽  
Glomerular Diseases

Abstract. Mutations in the Wilms' tumor suppressor gene (WT1) are linked with Denys-Drash syndrome (DDS), a rare childhood disease characterized by diffuse mesangial sclerosis and renal failure of early onset, XY pseudohermaphroditism, and high risk of Wilms' tumor. KTS (lysine-threonine-serine) splice site mutations in WT1 intron 9 have been described in patients with Frasier syndrome, another rare syndrome defined by focal and segmental glomerulosclerosis (FSGS), XY pseudohermaphroditism, and frequent occurrence of gonadoblastoma. Cases of Frasier syndrome raise the question whether splice site mutations may also be found in XX females with isolated FSGS. A girl (index case) presented with the nephrotic syndrome at 9 mo of age. The diagnosis of DDS was based on the finding of diffuse mesangial sclerosis in the kidney biopsy and of a XY karyotype. The index case's mother had had proteinuria since she was 6 years of age. A renal biopsy was performed when she was 28 and disclosed FSGS. The same splice site mutation in intron 9 (WT1 1228+5 G→A) involving one allele was found in the child and in her mother, but not in other members of the kindred (including the parents, the two brothers, and the two sisters of the index case's mother) who were free of renal symptoms. Quantification of WT1 +KTS/-KTS isoforms in the index case's father and one index case's maternal uncle showed a normal +KTS/-KTS ratio of 1.50. In contrast, the index case and her mother had a low ratio (0.40 and 0.34, respectively), within the range reported in Frasier syndrome. In conclusion, this study shows that the KTS splice site mutation is not specific for Frasier syndrome, but that it can also be found in DDS and in a normal female (XX) with FSGS, a woman who achieved normal pregnancy. It is suggested that WT1 splice site mutations should be sought in phenotypically normal females who present with FSGS or with related glomerulopathies of early onset.

scholarly journals Deficiency of FRAS1-related extracellular matrix 1 (FREM1) causes congenital diaphragmatic hernia in humans and mice

2012 ◽  
Vol 22 (5) ◽  
pp. 1026-1038 ◽  
Author(s):  
Tyler F Beck ◽  
Danielle Veenma ◽  
Oleg A Shchelochkov ◽  
Zhiyin Yu ◽  
Bum Jun Kim ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Splice Site ◽  
Critical Role ◽  
Splice Site Mutation ◽  
Site Mutation ◽  
Anterior Portion ◽  
Renal Anomalies ◽  
Truncating Mutation

Abstract Congenital diaphragmatic hernia (CDH) is a common life-threatening birth defect. Recessive mutations in the FRAS1-related extracellular matrix 1 (FREM1) gene have been shown to cause bifid nose with or without anorectal and renal anomalies (BNAR) syndrome and Manitoba oculotrichoanal (MOTA) syndrome, but have not been previously implicated in the development of CDH. We have identified a female child with an isolated left-sided posterolateral CDH covered by a membranous sac who had no features suggestive of BNAR or MOTA syndromes. This child carries a maternally-inherited ∼86 kb FREM1 deletion that affects the expression of FREM1's full-length transcripts and a paternally-inherited splice site mutation that causes activation of a cryptic splice site, leading to a shift in the reading frame and premature termination of all forms of the FREM1 protein. This suggests that recessive FREM1 mutations can cause isolated CDH in humans. Further evidence for the role of FREM1 in the development of CDH comes from an N-ethyl-N-nitrosourea -derived mouse strain, eyes2, which has a homozygous truncating mutation in Frem1. Frem1eyes2 mice have eye defects, renal agenesis and develop retrosternal diaphragmatic hernias which are covered by a membranous sac. We confirmed that Frem1 is expressed in the anterior portion of the developing diaphragm and found that Frem1eyes2 embryos had decreased levels of cell proliferation in their developing diaphragms when compared to wild-type embryos. We conclude that FREM1 plays a critical role in the development of the diaphragm and that FREM1 deficiency can cause CDH in both humans and mice.

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