Scientific background:

Summary: This transcription factor plays a key role in pancreatic beta cell function, so mutations in TCF1 cause maturity-onset diabetes of the young type 3 (MODY3).

Gene: 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.

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.

Clinical signs: 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.

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.

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

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

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		25 working days
		Effort		medium
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Multiplex Ligation-Dependent Probe Amplification
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	clinical test	Method		Carrier testing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.

Literature: 

Fajans SS et al. (2001) Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young.
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).
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.
Yamagata K et al. (1996) Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3)
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.
Yamada S et al. (1997) Identification of mutations in the hepatocyte nuclear factor (HNF)-1 alpha gene in Japanese subjects with IDDM.
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.
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.
Ellard S et al. (2000) Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young.
Bluteau O et al. (2002) Bi-allelic inactivation of TCF1 in hepatic adenomas.
Bjørkhaug L et al. (2003) Hepatocyte nuclear factor-1 alpha gene mutations and diabetes in Norway.
Rebouissou S et al. (2005) Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas.
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.
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).
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.
Hegele RA et al. (2000) Peroxisome proliferator-activated receptor-gamma2 P12A and type 2 diabetes in Canadian Oji-Cree.
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.
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.
Godart F et al. (2000) Identification of seven novel nucleotide variants in the hepatocyte nuclear factor-1alpha (TCF1) promoter region in MODY patients.
Chiu KC et al. (2000) The I27L amino acid polymorphism of hepatic nuclear factor-1alpha is associated with insulin resistance.
Babaya N et al. (2003) Association of I27L polymorphism of hepatocyte nuclear factor-1 alpha gene with high-density lipoprotein cholesterol level.
Yoshiuchi I et al. (2001) Analysis of a non-functional HNF-1alpha (TCF1) mutation in Japanese subjects with familial type 1 diabetes.
Collet C et al. (2002) Prevalence of the missense mutation Gly574Ser in the hepatocyte nuclear factor-1alpha in Africans with diabetes.
Bjørkhaug L et al. (2000) MODY associated with two novel hepatocyte nuclear factor-1alpha loss-of-function mutations (P112L and Q466X).
Xu JY et al. (2002) Mutations in the hepatocyte nuclear factor-1alpha gene in Chinese MODY families: prevalence and functional analysis.
Chèvre JC et al. (1998) Mutation screening in 18 Caucasian families suggest the existence of other MODY genes.
Rebouissou S et al. (2005) Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas.
Aguilar-Salinas CA et al. (2001) Early-onset type 2 diabetes: metabolic and genetic characterization in the mexican population.
De Simone V et al. (1991) LFB3, a heterodimer-forming homeoprotein of the LFB1 family, is expressed in specialized epithelia.
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.
Rey-Campos J et al. (1991) vHNF1 is a homeoprotein that activates transcription and forms heterodimers with HNF1.