Renal Cysts And Diabetes Syndrome

Cystic And Noncystic Kidney Disease

Nishigori et al. were the first to describe a family with renal cysts, proteinuria, and renal dysfunction that preceded the clinical presentation of diabetes. Although the exact role of HNF1 in kidney development awaits further examination, it is clear that HNF1B mutations can lead to abnormal nephron development. The latter process involves structures arising from the ureteric bud, giving rise to collecting ducts, the renal pelvis and ureter, and the metanephric mesenchyme responsible for the formation of the biggest part of the nephron. Both embryonic structures express HNF1, and HNF1 inactivation in mice leads to defective S-shaped body formation resulting in an enlarged Bowmans capsule and renal tubular dysgenesis. In addition to regulating genes involved in nephrogenesis per se, HNF1 affects several genes that are known to be involved in the pathogenesis of renal cystic disease. Examples are the PKD2 and PKHD1 genes that are mutated in polycystic kidney disease. HNF1 mutation in mice inhibited PKHD1 gene expression and induced renal cyst formation. Because HNF1 regulates several developmental and cystogenic pathways, there is a wide spectrum of developmental renal abnormalities in patients with HNF1B mutations.

The Relationship Between Simple Renal Cysts And Renal Function In Patients With Type 2 Diabetes

• Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China

Introduction: Simple renal cysts are the most common acquired cystic kidney disease, but the relationship between SRCs and renal function has not been clarified in patients with type 2 diabetes mellitus .

Methods: A retrospective study was conducted to analyze the clinical features of renal cysts and ultrasound data of the kidney in 4,304 patients with T2DM.

Results: The prevalence of SRCs in patients with T2DM was 21.1%. Compared to patients with no SRCs, patients with SRCs had worse renal function . After adjusting the confounders, SRC was related to estimated glomerular filtration rate in patients with T2DM . Age, gout, proteinuria, cerebrovascular disease , and increased serum phosphorus levels were associated with SRCs in patients with T2DM.

: SRCs are associated with worse renal function in patients with T2DM. More attention should be paid to gout, proteinuria, CVD, serum phosphorus levels, and renal function in T2DM patients with SRCs.

Amplification Of Illegitimately Transcribed Mrna From Transformed Lymphoblastoid Cell Lines

Total RNA was extracted from approximately 1×106 EBV-transformed lymphoblastoid cells using the Perfect RNA Mini RNA kit according to manufacturers instructions. Complementary DNA was synthesised from 5 µg of the total RNA using the Thermoscript RT-PCR system according to the manufacturers instructions. The incubation temperature was 50 °C. RT-PCR reactions were set up in triplicate in a two-round nested PCR with three overlapping fragments covering the entireHNF-1 cDNA from mutation-bearing cell lines and from unaffected controls . We used 2 µl of each cDNA in each first-step PCR reaction. For the second round, 1 µl of a 1:10 dilution was used. Conditions for both rounds of PCR were as follows: 3 min at 95 °C initial denaturation, followed by 35 cycles of 1 min at 95 °C, 1 min at 55 °C, 2 min at 72 °C and a final 10-min extension at 72 °C. We used 2.5 U of Taq polymerase per reaction.

Table 1 Primers used for nested RT-PCR of HNF-1

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Functional Studies On Hnf

Functional studies have been reported on nine HNF-1 mutants. These mutants include one missense mutation, S151P with a change from serine to proline within the DNA-binding region, and two nonsense and five frameshift mutations, all of which are truncating mutations. Seven of these mutants occur within exons 13 and lack all or part of the domains involved in DNA binding and all fail to bind DNA. Two of the mutants in exons 4 and 5 have an intact DNA-binding domain and they bind DNA as efficiently as wild-type protein. The presence of intact DNA binding correlates with the ability to form dimers and transactivate a reporter gene. These mutants have been introduced into Xenopus embryos and all interfere with the development of the pronephros, which is the first kidney in the amphibian. Six of the mutants led to an enlargement of the pronephros. All these mutants lack DNA binding and have no transactivation potential. Three mutants led to a partial or complete agenesis of the pronephros. These included the two mutants with intact DNA binding but also the mutant R137-K161del, which has an in-frame deletion of 24 amino acids within the DNA-binding domain and, thus, fails to bind DNA, although the transactivation domain is intact. The functional studies in Xenopus may define features of the HNF-1 protein which are not detected by in vitro studies .

Diabetes And Exocrine Pancreas Dysfunction

As described above, HNF1B mutations were first described as a cause of MODY. HNF1 has structural similarity to HNF1, the affected gene in the most common type of MODY . Horikawa et al. sequenced the HNF1 transcription factor in 57 patients with MODY and found 1 patient with an HNF1B loss-of-function mutation. HNF1 is thought to play an important role in early development and differentiation of the pancreas. It regulates the expression of key pancreatic proteins, including the HNF4A and SLC2A2 genes, the latter encoding the glucose transporter GLUT2.HNF1B mutations can therefore result not only in pancreatic cell dysfunction, leading to diabetes mellitus, but also pancreatic atrophy and exocrine pancreatic dysfunction. Pancreatic atrophy affecting either the head or body of the pancreas is frequently observed on computed tomography in patients with HNF1B mutations in combination with exocrine pancreatic dysfunction, which is often subclinical. Patients mostly present with diabetes in their early adulthood but with a large variation from the neonatal period to late middle age., Endogenous insulin production is present and patients with diabetes are not obligatorily insulin dependent. However, the majority of patients eventually require insulin therapy for an adequate glycemic control, which is not the case for HNF1-associated MODY. Overall, HNF1B mutations are an infrequent cause of MODY, occurring in < 1% of cases.

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Rcc And Other Malignancies

Case studies suggest that lack of HNF1 expression is related to chromophobe RCC., Chromophobe RCC is a rare renal cancer that has relatively pale cytoplasm under the microscope, as opposed to the clear cytoplasm in clear cell RCC. This raises the question of whether we should screen patients with HNF1B mutations for renal tumors. Several reports have also suggested a role for HNF1 as a tumor marker in different tumors such as hepatocellular carcinoma,, gynecologic tumors,, and prostate carcinoma. The clinical significance of these findings for patients with HNF1B mutations is currently unknown but deserves further attention.

Genetic Causes Of Mody

To date it has been proposed that pathogenic variants in at least 14 genes cause MODY. The genes and associated clinical features are summarized in .

The four most common causes of MODY are the following:

• GCK-MODY and HNF1A-MODY , each accounting for 30%-60% of all MODY. The prevalence of GCK-MODY has been estimated at 1:1,000 individuals however, among all causes of MODY, the prevalence of GCK-MODY is higher in some countries most likely due to biased ascertainment of children compared to adults.
• HNF4A-MODY and HNF1B-MODY , together accounting for about 10% of all MODY

Approximately 20% of all MODY has been attributed to pathogenic variants in ten other genes some of which were designated before the availability of large-scale genetic testing and thus may be incorrectly associated with MODY. Molecular genetic testing of large numbers of individuals with possible MODY as well as other investigations are needed to determine the significance of variants previously inferred to be pathogenic based on other methods.

A portion of MODY may be caused by pathogenic variants in yet-to-be-identified genes or complex molecular alterations in the known MODY-related genes that were not detected by previous genetic testing methods .

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Renal Cysts And Diabetes Syndrome

Synonyms

FJHN atypical Familial hypoplastic, glomerulocystic kidney Glomerulocystic kidney disease, hypoplastic type Hyperuricemic nephropathy, familial juvenile, atypical MODY type 5 Maturity-onset diabetes of the young, type 5 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT, 3

Modes of inheritance

MedGen UID: 141047, Concept ID: C0443147, Intellectual Product

A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.

Full text of GeneReview :

Which Individuals Should Be Screened For Hnf1 Mutations

In conclusion, HNF1-related disease is a variable multisystem disorder with limited genotype-phenotype correlation, with specific significance to the nephrologist. It is likely that an unknown but potentially large percentage of HNF1-associated kidney disease is currently not being recognized or is misdiagnosed. In addition, there can be a considerable diagnostic delay before the disease is eventually recognized, as exemplified in some of the presented cases. Although no causal therapy is currently available, diagnosing the syndrome is important. Early recognition makes screening for diabetes, renal function decline, hypomagnesemia, and associated hypokalemia possible, and it may prevent unnecessary examinations and biopsies. In addition, genetic counseling should be offered to patients and their family members.

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Citation Doi & Article Data

Citation:DOI:Dr Francis DengRevisions:see full revision historySystems:

• Renal cysts and diabetes syndrome
• HNF1B-associated disease
• Maturity-onset diabetes of the young, type 5

Renal cysts and diabetes syndrome , also known as maturity-onset diabetes of the young, type 5 , refers to the combination of renal cortical cysts and diabetes mellitus in patients with mutations in the HNF1B gene. When renal cysts are associated with these mutations without disturbances in glucose metabolism, the term HNF1B-associated kidney disease may be used.

Renal Cysts And Diabetes Syndrome Autism And Schizophrenia Linked

Researchers have uncovered a small genomic deletion in patients with autism spectrum disorders and schizophrenia.

Researchers whose study results were published yesterday in the American Journal of Human Genetics have uncovered a small genomic deletion in patients with autism spectrum disorders and schizophrenia. The region in which the deletion occurs also includes a gene that when mutated is know to cause renal cysts and diabetes syndrome .

âThe genetic overlap between ASD and schizophrenia, both of which have a high heritability, has been the focus of several recent studies however, no single specific genetic cause accounts for more than 1%-2% of cases,â said lead author Dr. Daniel Moreno-De-Luca.

Working with a team of investigators, Moreno-De-Luca analyzed the DNA of 23,000 patients with ASD, developmental delay, or schizophrenia to find DNA duplications or deletions . In 24 patients, the researchers found the same deletion on chromosome 17 , a CNV that was absent in 52,448 controls.

âWe calculate the risk for this combined sample to be at least 13.58, and probably much higher,â said Dr. David H. Ledbetter, Emory University.

The gene highlighted in the current study is one of 15 contained within the deletion. Whats interesting is that many patients with ASD in the study had a family history of kidney

disease and/or diabetes. Additionally, patients with RCAD often present with neurodevelopmental disorders.

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Clinical Characteristics Of Mody

Maturity-onset diabetes of the young is a group of inherited disorders of non-autoimmune diabetes mellitus which usually present in adolescence or young adulthood.

A clinical diagnosis of MODY can be suspected in individuals with:

• Early-onset diabetes in adolescence or young adulthood
• Features atypical for type 1 diabetes mellitus including the following:
• Absence of pancreatic islet autoantibodies
• Evidence of endogenous insulin production beyond the honeymoon period
• Measurable C-peptide in the presence of hyperglycemia
• Low insulin requirement for treatment
• Lack of ketoacidosis when insulin is omitted from treatment

Renal Cysts And Diabetes Syndrome Rcad

Alternative titles symbols

MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 5 MODY5HYPERURICEMIC NEPHROPATHY, FAMILIAL JUVENILE, ATYPICALFJHN, ATYPICALTUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT, 3 ADTKD3GLOMERULOCYSTIC KIDNEY DISEASE, HYPOPLASTIC TYPEGLOMERULOCYSTIC KIDNEY, FAMILIAL HYPOPLASTICCONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT WITH DIABETESCAKUT WITH DIABETES

GROWTH ABDOMEN Liver Pancreas GENITOURINARY External Genitalia Internal Genitalia Kidneys SKELETAL ENDOCRINE FEATURES LABORATORY ABNORMALITIES MISCELLANEOUS MOLECULAR BASIS

Tubulointerstitial kidney disease ââ 5 Entries

â¼TEXT

A number sign is used with this entry because of evidence that renal cysts and diabetes syndrome is caused by heterozygous mutation in the TCF2 gene on chromosome 17q12.

â¼Description

For a phenotypic description and a discussion of genetic heterogeneity of MODY, see .

For a discussion of genetic heterogeneity of ADTKD and a discussion of the revised nomenclature of these disorders, see ADTKD1 .

The renal abnormalities are part of a spectrum of malformations known as congenital anomalies of the kidney and urinary tract .

â¼Clinical Features

reported a Japanese family in which 3 sibs developed MODY at ages 14, 10, and 15 years, respectively. Their mother and maternal uncle developed diabetes at ages 40 and 60, respectively their father developed diabetes at age 50. A nonspecific nephropathy was described.

Clinical Variability

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Abnormal Liver Function Tests

Elevated liver enzymes are frequent in patients with HNF-1 mutations . This has been characterized by elevation of alanine aminotransferase and -glutamyl transpeptidase without jaundice or liver insufficiency. There have been no liver cysts or other clear aetiological markers seen on ultrasound examination, although in one subject the ultrasound examination suggested liver fibrosis . There have been no reports of liver histology, other than in a 7-month-old child where the histology was normal .

Prenatal Identification Of A Pathogenic In

Prenatal panel sequencing in individual I1 revealed a novel heterozygous 3-bp deletion in exon 3 of HNF1B , resulting in an in-frame deletion of the highly conserved AA glycine at position 239 ) . The identified indel variant was not present in the Genome Aggregation Database and was computationally predicted to be deleterious. A potential splice effect was not detected . The c.715_717del variant could not be identified in DNA from peripheral blood lymphocytes of both parents and thus likely arose de novo. Structural modeling based on the crystal structure of the HNF1B protein showed that the glycine at position 239 lies in an alpha-helix motif of the homeodomain, which has DNA-binding function. The deletion of Gly is predicted to disrupt two neighboring AAs involved in binding to DNA . Two missense variants and c.716G> A, p.) affecting the same AA were reported in a boy with bilateral renal cysts, kidney failure, and diabetes in childhood and in a girl with MODY, renal cysts in the right kidney, agenesis of left kidney, and pancreas atrophy, respectively. Furthermore, a variant affecting the neighboring residue Trp238 ) was described as pathogenic . On the basis of the ACMG criteria , we classified the identified variant as pathogenic .

Figure 2HNF1BHNF1B

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Risk Assessment And Surveillance Of At

Genetic counseling is the process of providing individuals and families withinformation on the nature, mode of inheritance, and implications of genetic disorders to help themmake informed medical and personal decisions. The following section deals with geneticrisk assessment and the use of family history and genetic testing to clarify geneticstatus for family members it is not meant to address all personal, cultural, orethical issues that may arise or to substitute for consultation with a geneticsprofessional. ED.

The advantages of early clarification of the genetic status of asymptomatic family members at risk for MODY:

• Routine surveillance to identify hyperglycemia enables prompt and appropriate treatment based on the type of MODY .
• For those at increased risk, early intervention reduces the long-term risk of hyperglycemia-related microvascular and macrovascular complications .
• Families with individuals with MODY as well as the much more common type 1 and type 2 diabetes can be assured that each individual will receive the appropriate surveillance and therapy for his/her diagnosis.

Studies have shown that family members at risk for MODY are generally in favor of early predictive genetic testing .

Vata Pitta And Kapha Dosha Nephrotic Syndrome

Ayurveda assesses any disease in terms of Dosha, Dushya, and Adhishthana of the disease and the capabilities of the patient. After proper identification, appropriate therapeutic interventions are planned. The contemporary system of treatment is costly. There is always a need to establish affordable medical care with no side effects. Our ancient system of treatment-ayurveda is available with sustainable remedial measures. When we try to understand kidney disease as per the view of Ayurveda, we find that for all types of urine disorders, Vata dosha is the causative factor collaborating with Pitta and Kapha. The proportion of vata, pitta and Kapha dosha varies from person to person. Hence, a person-specific treatment needs to be applied considering Doshas. A general proposed line of kidney failure treatment is virechana.

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Urinary Proteome Signature Of Renal Cysts And Diabetes Syndrome In Children

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