Scientific background:

Summary: After removal of the precursor signal peptide, proinsulin is post-translationally cleaved into three peptides: the B chain and A chain peptides, which are covalently linked via two disulfide bonds to form insulin, and C-peptide. Binding of insulin to the insulin receptor (INSR) stimulates glucose uptake. A multitude of mutant alleles with phenotypic effects have been identified. There is a read-through gene, INS-IGF2, which overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region. Alternative splicing results in multiple transcript variants. [provided by RefSeq]

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	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: 

Abney M et al. (2002) Quantitative-trait homozygosity and association mapping and empirical genomewide significance in large, complex pedigrees: fasting serum-insulin level in the Hutterites.
Awata T et al. (2007) Insulin gene/IDDM2 locus in Japanese type 1 diabetes: contribution of class I alleles and influence of class I subdivision in susceptibility to type 1 diabetes.
Barbetti F et al. (1990) Two unrelated patients with familial hyperproinsulinemia due to a mutation substituting histidine for arginine at position 65 in the proinsulin molecule: identification of the mutation by direct sequencing of genomic deoxyribonucleic acid amplified by polymerase chain reaction.
Bell GI et al. (1980) Sequence of the human insulin gene.
Bell GI et al. (1979) Nucleotide sequence of a cDNA clone encoding human preproinsulin.
Carroll RJ et al. (1988) A mutant human proinsulin is secreted from islets of Langerhans in increased amounts via an unregulated pathway.
Chaganti RS et al. (1985) Germ-line chromosomal localization of genes in chromosome 11p linkage: parathyroid hormone, beta-globin, c-Ha-ras-1, and insulin.
Chan SJ et al. (1987) A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia.
Cheung AT et al. (2000) Glucose-dependent insulin release from genetically engineered K cells.
Collinet M et al. (1998) Familial hyperproinsulinaemia due to a mutation substituting histidine for arginine at position 65 in proinsulin: identification of the mutation by restriction enzyme mapping.
Colombo C et al. (2008) Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus.
Dandona P et al. (2001) Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect?
Davies PO et al. (1994) Genetic reassignment of the insulin-1 (Ins1) gene to distal mouse chromosome 19.
Deltour L et al. (1993) Differential expression of the two nonallelic proinsulin genes in the developing mouse embryo.
Edghill EL et al. (2008) Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.
Elbein SC et al. (1985) Hyperproinsulinemia in a family with a proposed defect in conversion is linked to the insulin gene.
Farris W et al. (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.
Frøsig C et al. (2007) Effects of endurance exercise training on insulin signaling in human skeletal muscle: interactions at the level of phosphatidylinositol 3-kinase, Akt, and AS160.
Gabbay KH et al. (1980) The insulinopathies.
Gabbay KH et al. (1979) Familial hyperproinsulinemia: partial characterization of circulating proinsulin-like material.
Gabbay KH et al. (1976) Familial hyperproinsulinemia. An autosomal dominant defect.
Given BD et al. (1980) Diabetes due to secretion of an abnormal insulin.
Gruppuso PA et al. (1984) Familial hyperproinsulinemia due to a proposed defect in conversion of proinsulin to insulin.
Haneda M et al. (1983) Studies on mutant human insulin genes: identification and sequence analysis of a gene encoding [SerB24]insulin.
Haneda M et al. (1986) Low frequency of the large insertion in the human insulin gene in Japanese.
Haneda M et al. (1984) Familial hyperinsulinemia due to a structurally abnormal insulin. Definition of an emerging new clinical syndrome.
Harper ME et al. (1981) Localization of the human insulin gene to the distal end of the short arm of chromosome 11.
Heude B et al. (2006) The insulin gene variable number of tandem repeat: associations and interactions with childhood body fat mass and insulin secretion in normal children.
Hua QX et al. (1993) Paradoxical structure and function in a mutant human insulin associated with diabetes mellitus.
Ibáñez L et al. (2001) Insulin gene variable number of tandem repeat genotype and the low birth weight, precocious pubarche, and hyperinsulinism sequence.
Jaquet D et al. (2000) Insulin resistance early in adulthood in subjects born with intrauterine growth retardation.
Jones JM et al. (1992) Localization of insulin-2 (Ins-2) and the obesity mutant tubby (tub) to distinct regions of mouse chromosome 7.
Kayo T et al. (1998) Mapping of murine diabetogenic gene mody on chromosome 7 at D7Mit258 and its involvement in pancreatic islet and beta cell development during the perinatal period.
Kwok SC et al. (1981) Loss of a restriction endonuclease cleavage site in the gene of a structurally abnormal human insulin.
Kwok SC et al. (1983) Identification of a point mutation in the human insulin gene giving rise to a structurally abnormal insulin (insulin Chicago).
Lebo RV et al. (1983) Recombination within and between the human insulin and beta-globin gene loci.
Lebo RV et al. (1982) Assigning the polymorphic human insulin gene to the short arm of chromosome 11 by chromosome sorting.
Le Stunff C et al. (2001) Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity.
Le Stunff C et al. (2000) The insulin gene VNTR is associated with fasting insulin levels and development of juvenile obesity.
Lichter P et al. (1990) High-resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones.
Lomedico P et al. (1979) The structure and evolution of the two nonallelic rat preproinsulin genes.
Meigs JB et al. (2005) The insulin gene variable number tandem repeat and risk of type 2 diabetes in a population-based sample of families and unrelated men and women.
Meyers DA et al. (1986) Multipoint mapping studies of the beta-globin, insulin, and c-Ha-ras-1 loci on 11p.
Michalova K et al. (1988) Chromosome localization of the human insulin gene in transgenic mouse lines.
Molven A et al. (2008) Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes.
Nanjo K et al. (1986) Diabetes due to secretion of a structurally abnormal insulin (insulin Wakayama). Clinical and functional characteristics of [LeuA3] insulin.
Narendran P et al. (2006) Proinsulin is encoded by an RNA splice variant in human blood myeloid cells.
Obici S et al. (2002) Hypothalamic insulin signaling is required for inhibition of glucose production.
Olansky L et al. (1992) A variant insulin promoter in non-insulin-dependent diabetes mellitus.
Osawa H et al. (2001) Systematic search for single nucleotide polymorphisms in the insulin gene: evidence for a high frequency of -23T-->A in Japanese subjects.
Owerbach D et al. (1980) The insulin gene is located on chromosome 11 in humans.
Polak M et al. (2008) Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy: a report from the French ND (Neonatal Diabetes) Study Group.
Robbins DC et al. (1981) A human proinsulin variant at arginine 65.
Robbins DC et al. (1984) Familial hyperproinsulinemia. Two cohorts secreting indistinguishable type II intermediates of proinsulin conversion.
Robbins DC et al. (1984) Biologic and clinical importance of proinsulin.
Robinson GL et al. (1994) Isolation and characterization of a novel transcription factor that binds to and activates insulin control element-mediated expression.
Röder ME et al. (1996) Hyperproinsulinemia in a three-generation Caucasian family due to mutant proinsulin (Arg65-His) not associated with imparied glucose tolerance: the contribution of mutant proinsulin to insulin bioactivity.
Rodríguez S et al. (2004) Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits.
Rotwein P et al. (1981) Polymorphism in the 5'-flanking region of the human insulin gene and its possible relation to type 2 diabetes.
Rotwein P et al. (1986) Genetic analysis of the hypervariable region flanking the human insulin gene.
Sakura H et al. (1986) Structurally abnormal insulin in a diabetic patient. Characterization of the mutant insulin A3 (Val----Leu) isolated from the pancreas.
Santoro N et al. (2006) Insulin gene variable number of tandem repeats (INS VNTR) genotype and metabolic syndrome in childhood obesity.
Schwartz GP et al. (1987) A superactive insulin: [B10-aspartic acid]insulin(human).
Seino S et al. (1985) Identification of insulin variants in patients with hyperinsulinemia by reversed-phase, high-performance liquid chromatography.
Selden RF et al. (1987) Regulation of insulin-gene expression. Implications for gene therapy.
Shibasaki Y et al. (1985) Posttranslational cleavage of proinsulin is blocked by a point mutation in familial hyperproinsulinemia.
Shoelson S et al. (1983) Identification of a mutant human insulin predicted to contain a serine-for-phenylalanine substitution.
Shoelson S et al. (1983) Three mutant insulins in man.
Soares MB et al. (1985) RNA-mediated gene duplication: the rat preproinsulin I gene is a functional retroposon.
Stead JD et al. (2000) Allele diversity and germline mutation at the insulin minisatellite.
Steiner DF et al. (1976) Editorial: Errors in insulin biosynthesis.
Steiner DF et al. (1985) Structure and evolution of the insulin gene.
Steiner DF et al. (1967) The biosynthesis of insulin and a probable precursor of insulin by a human islet cell adenoma.
Støy J et al. (2007) Insulin gene mutations as a cause of permanent neonatal diabetes.
Sures I et al. (1980) Nucleotide sequence of human preproinsulin complementary DNA.
Tager H et al. (1979) A structurally abnormal insulin causing human diabetes.
Todd S et al. (1985) Genes for insulin I and II, parathyroid hormone, and calcitonin are on rat chromosome 1.
Ueki K et al. (2006) Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes.
Ullrich A et al. (1980) Genetic variation in the human insulin gene.
Vafiadis P et al. (2001) Class III alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes.
Vinik AI et al. (1986) Familial hyperinsulinemia associated with secretion of an abnormal insulin, and coexistence of insulin resistance in the propositus.
Wang J et al. (1999) A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse.
Warren-Perry MG et al. (1997) A novel point mutation in the insulin gene giving rise to hyperproinsulinemia.
White R et al. () Construction of linkage maps with DNA markers for human chromosomes.
Williams LG et al. (1985) Allelic variation adjacent to the human insulin and apolipoprotein C-II genes in different ethnic groups.
Yano H et al. (1992) A novel point mutation in the human insulin gene giving rise to hyperproinsulinemia (proinsulin Kyoto).
Yoshioka M et al. (1997) A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice.