Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Transcription factor HNF1alpha

This transcription factor plays a key role in pancreatic beta cell function, so mutations in TCF1 cause autosomal dominant maturity-onset diabetes of the young type 3 (MODY3) and hyperinsulinemic hypoglycemia. Some mutations are also associated with renal dysplasia and hypopituitarism.

Epidemiology

MODY 3 Diabetes is one of the most common types of MODY. About 10% of MODY in Germany is caused by mutations of this transcription factor. These mutations could be found worldwide.

Gene Structure

The gene also known as hepatic nuclear factor is now called TCF1. Locus is on chromosome 12 (12q24.2). Size is about 24kb. Is consists of 12 Exons. 10 of them are translated.

Phenotype

Mutations in this gene are responsible for autosomal dominant MODY 3 diabetes. Biochemically the picture is similar to type 2 diabetes but manifestation is early in life and there is no metabolic syndrome. In contrast to MODY 2 diabetes this type of MODY is progressive. Over the time Patients require insulin therapy and develop diabetic injuries The diabetes becomes apparent in situations of metabolic stress i.e. in pregnancy or during medication with glucocorticoids.

Pathology

The protein product of this gene is a transcription factor involved in the regulation of many different genes. The exact mechanism leading to diabetes is not known.

Test Strategy

Patients with family history and laboratory data suspect for MODY diabetes. Screening of family member in a known MODY family.

Interpretation

The detection of a mutation in this gene is a prerequisite for the diagnosis.

Genetests:

Clinic Method Carrier testing
Turnaround 5 days
Specimen type genomic DNA
Clinic Method Multiplex Ligation-Dependent Probe Amplification
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25 days
Specimen type genomic DNA

Related Diseases:

MODY3 diabetes
HNF1A
Hyperinsulinemic hypoglycemia
HNF1A
HNF4A
Hyperinsulinemic hypoglycemia 1
ABCC8
Hyperinsulinemic hypoglycemia 2
KCNJ11
Hyperinsulinemic hypoglycemia 3
GCK
Hyperinsulinemic hypoglycemia 4
HADH
Hyperinsulinemic hypoglycemia 5
INSR
Hyperinsulinemic hypoglycemia 6
GLUD1
Hyperinsulinemic hypoglycemia 7
SLC16A1
Polycystic kidney disease with hyperinsulinemic hypoglycemia
PMM2
Nonpapillary renal cell carcinoma
DIRC2
FLCN
HNF1A
HNF1B
OGG1
RNF139
VHL
Renal dysplasia with hypopituitarism and diabetes
HNF1A

References:

1.

Miedzybrodzka Z et al. (1999) Non-penetrance in a MODY 3 family with a mutation in the hepatic nuclear factor 1alpha gene: implications for predictive testing.

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2.

Godart F et al. (2000) Identification of seven novel nucleotide variants in the hepatocyte nuclear factor-1alpha (TCF1) promoter region in MODY patients.

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3.

Hegele RA et al. (2000) Peroxisome proliferator-activated receptor-gamma2 P12A and type 2 diabetes in Canadian Oji-Cree.

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4.

Chiu KC et al. (2000) The I27L amino acid polymorphism of hepatic nuclear factor-1alpha is associated with insulin resistance.

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5.

Ellard S et al. (2000) Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young.

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6.

Bjørkhaug L et al. (2000) MODY associated with two novel hepatocyte nuclear factor-1alpha loss-of-function mutations (P112L and Q466X).

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7.

Aguilar-Salinas CA et al. (2001) Early-onset type 2 diabetes: metabolic and genetic characterization in the mexican population.

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8.

Ryffel GU et al. (2001) Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF)1 and HNF4 families: functional and pathological consequences.

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9.

Fajans SS et al. (2001) Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young.

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10.

Yoshiuchi I et al. (2001) Analysis of a non-functional HNF-1alpha (TCF1) mutation in Japanese subjects with familial type 1 diabetes.

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11.

Triggs-Raine BL et al. (2002) HNF-1alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community.

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12.

Collet C et al. (2002) Prevalence of the missense mutation Gly574Ser in the hepatocyte nuclear factor-1alpha in Africans with diabetes.

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13.

Xu JY et al. (2002) Mutations in the hepatocyte nuclear factor-1alpha gene in Chinese MODY families: prevalence and functional analysis.

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14.

Bluteau O et al. (2002) Bi-allelic inactivation of TCF1 in hepatic adenomas.

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15.

Bjørkhaug L et al. (2003) Hepatocyte nuclear factor-1 alpha gene mutations and diabetes in Norway.

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16.

Babaya N et al. (2003) Association of I27L polymorphism of hepatocyte nuclear factor-1 alpha gene with high-density lipoprotein cholesterol level.

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17.

Yamagata K et al. (2003) Regulation of pancreatic beta-cell function by the HNF transcription network: lessons from maturity-onset diabetes of the young (MODY).

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18.

Rebouissou S et al. (2005) Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas.

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19.

De Simone V et al. (1991) LFB3, a heterodimer-forming homeoprotein of the LFB1 family, is expressed in specialized epithelia.

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20.

Rey-Campos J et al. (1991) vHNF1 is a homeoprotein that activates transcription and forms heterodimers with HNF1.

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21.

Mendel DB et al. (1991) HNF-1 alpha and HNF-1 beta (vHNF-1) share dimerization and homeo domains, but not activation domains, and form heterodimers in vitro.

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22.

Stanescu DE et al. (2012) Novel Presentations of Congenital Hyperinsulinism due to Mutations in the MODY genes: HNF1A and HNF4A.

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23.

Byrne MM et al. (1996) Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12.

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24.

Yamagata K et al. (1996) Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3)

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25.

Kaisaki PJ et al. (1997) Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and early-onset NIDDM: evidence for a mutational hotspot in exon 4.

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26.

Hansen T et al. (1997) Novel MODY3 mutations in the hepatocyte nuclear factor-1alpha gene: evidence for a hyperexcitability of pancreatic beta-cells to intravenous secretagogues in a glucose-tolerant carrier of a P447L mutation.

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27.

Vaxillaire M et al. (1997) Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3).

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28.

Yamada S et al. (1997) Identification of mutations in the hepatocyte nuclear factor (HNF)-1 alpha gene in Japanese subjects with IDDM.

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29.

Gragnoli C et al. (1997) Maturity-onset diabetes of the young due to a mutation in the hepatocyte nuclear factor-4 alpha binding site in the promoter of the hepatocyte nuclear factor-1 alpha gene.

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30.

Frayling TM et al. (1997) A rapid screening method for hepatocyte nuclear factor 1 alpha frameshift mutations; prevalence in maturity-onset diabetes of the young and late-onset non-insulin dependent diabetes.

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31.

Chèvre JC et al. (1998) Mutation screening in 18 Caucasian families suggest the existence of other MODY genes.

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Update: Sept. 26, 2018