Alternative titles; symbols
HGNC Approved Gene Symbol: PTF1A
Cytogenetic location: 10p12.2 Genomic coordinates (GRCh38) : 10:23,192,312-23,194,245 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p12.2 | Pancreatic agenesis 2 | 615935 | Autosomal recessive | 3 |
| Pancreatic and cerebellar agenesis | 609069 | Autosomal recessive | 3 |
The gene PTF1A encodes a basic helix-loop-helix protein of 48 kD that is a sequence-specific DNA-binding subunit of the trimeric pancreas transcription factor-1 (PTF1) (Krapp et al. (1996, 1998)). Krapp et al. (1996) cloned the PTF1A gene.
Pancreas development begins with the formation of buds at specific sites in the embryonic foregut endoderm. Kawaguchi et al. (2002) used in vivo recombination-based lineage tracing in mice to show that Ptf1a (also known as PTF1-p48) is expressed at these early stages in the progenitors of pancreatic ducts, exocrine and endocrine cells, rather than being an exocrine-specific gene as previously described (Krapp et al., 1996; Adell et al., 2000; Rose et al., 2001). Moreover, inactivation of Ptf1a switches the character of pancreatic progenitors such that their progeny proliferate in and adopt the normal fates of duodenal epithelium, including its stem-cell compartment. Consistent with their proposal that Ptf1a supports the specification of precursors of all 3 pancreatic cell types, Kawaguchi et al. (2002) found that transgene-based expression of Pdx1 (600733), a gene essential to pancreas formation, under the control of Ptf1a cis-regulatory sequences restored pancreas tissue to Pdx1-null mice that otherwise lacked mature exocrine and endocrine cells because of an early arrest in organogenesis. The experiments of Kawaguchi et al. (2002) provided evidence that Ptf1a expression is specifically connected to the acquisition of pancreatic fate by undifferentiated foregut endoderm.
Masui et al. (2007) found that Ptf1a interacted with Rbpj (RBPSUH; 147183) within a stable trimeric DNA-binding PTF1 complex during early pancreatic development in mouse. As acinar cell development began, Rbpj was swapped for Rbpjl, the constitutively active, pancreas-restricted Rbpj paralog, and Rbpjl was a direct target of the PTF1 complex. At the onset of acinar cell development, when the Rbpjl gene was first induced, a PTF1 complex containing Rbpj bound to the Rbpjl promoter. As development proceeded, Rbpjl gradually replaced Rbpj in the PTF1 complex bound to the Rbpjl promoter and appeared on the PTF1 complex-binding sites on the promoters of other acinar-specific genes, including those for secretory digestive enzymes. Introduction of a Ptf1a mutant unable to bind Rbpj truncated pancreatic development at an immature stage, without the formation of acini or islets.
Pancreatic and Cerebellar Agenesis
Individuals with permanent neonatal diabetes mellitus (PNDM; see 606176) usually present within the first 3 months of life and require insulin treatment. PNDM is both phenotypically and genetically heterogeneous. By genomewide linkage search, Sellick et al. (2003) identified a locus on 10p13-p12.1 involved in PNDM associated with pancreatic and cerebellar agenesis (PACA; 609069) in a consanguineous Pakistani family (Hoveyda et al., 1999). The linkage to specific single-nucleotide polymorphism (SNP) markers was confirmed with microsatellite markers and replicated in a second family of northern European descent segregating an identical phenotype. Sellick et al. (2004) selected 3 genes that mapped to the region of linkage for candidate gene screening based on their expression in human or mouse pancreatic and cerebellar tissue and implied biologic function. These 3 genes were PIP5K2A (603140), PTF1A, and CACNB2 (600003). Sellick et al. (2004) identified the mutations 886C-T (607194.0001) and 705insG (607194.0002) in the PTF1A gene as disease-causing sequence changes. Both mutations caused truncation of the expressed PTF1A protein C-terminal to the basic helix-loop-helix domain. Reporter gene studies using a minimal PTF1A deletion mutant indicated that the deleted region defines a new domain that is crucial for the function of the protein. PTF1A was known to have a role in mammalian pancreatic development; the clinical phenotype of the affected individuals implicated the protein also as a key regulator of cerebellar neurogenesis. Sellick et al. (2004) confirmed the essential role of PTF1A in normal cerebellar development by detailed neuropathologic analysis of Ptf1a -/- mice.
Isolated Pancreatic Agenesis
By whole-genome sequencing of 2 probands from unrelated multiplex consanguineous families with isolated pancreatic agenesis mapping to chromosome 10p12 (PAGEN2; 615935), Weedon et al. (2014) identified homozygosity in both patients for the same variant: an A-G transition on chromosome 10 at g.23508437 (GRCh37), located about 25 kb downstream of the PTF1A gene within an approximately 400-bp evolutionarily conserved region. Sequencing of this putative pancreatic developmental enhancer in 19 additional probands with PAGEN revealed recessive mutations in 7 of 10 probands with isolated pancreatic agenesis as well as in 1 patient who also had fatal cholestatic liver failure. Overall, 9 affected individuals from 6 unrelated families of Syrian, Lebanese, Kurdish, and Turkish ancestry were homozygous for the same chromosome 10 mutation, g.23508437A-G, as part of a shared 1.2-Mb haplotype. In addition, a sporadic patient from Pakistan was homozygous for g.23508363A-G; a sporadic patient from Germany was compound heterozygous for g.23508365A-G and g.23508446A-C; and 2 Arabian sibs were homozygous for a 7.6-kb deletion that included the entire putative enhancer. Finally, a sporadic Costa Rican patient who had pancreatic agenesis with fatal cholestatic liver failure was homozygous for g.23508302A-G. Testing of parents and sibs demonstrated cosegregation of the mutations with diabetes and exocrine insufficiency, and none of the mutations were found in 299 controls, in 1,092 individuals from the 1000 Genomes Project database, or in the dbSNP (build 137) database. Functional analysis demonstrated that the approximately 400-bp region acts as a developmental enhancer of PTF1A in human embryonic pancreatic progenitor cells and that the 6 mutations abolish enhancer activity: 3 of the base-substitution mutations disrupt binding sites for FOXA2 (600288) and 1 disrupts a binding site for PDX1 (600733), whereas the remaining point mutation disrupts the affinity of an uncharacterized sequence-specific DNA-binding protein present in mouse pancreatic progenitors. Amberger (2014) noted that the mutations identified by Weedon et al. (2014) are located within C10ORF115, a long noncoding RNA.
In the consanguineous Pakistani family with pancreatic and cerebellar hypoplasia/agenesis (PACA; 609069) described by Hoveyda et al. (1999), Sellick et al. (2004) demonstrated homozygosity for an 886C-T transition in exon 2 of the PTF1A gene causing a nonsense mutation (arg296 to stop; R296X). The mutation caused truncation of the C-terminal 32 amino acids of the expressed protein. Circulating insulin and C peptide levels were measurable, albeit at very low levels, in all affected individuals.
In a consanguineous family of northern European descent, Sellick et al. (2004) demonstrated that a patient with pancreatic and cerebellar aplasia/hypoplasia (PACA; 609069) was homozygous for a single-basepair insertion (705insG) in exon 1 of the PTF1A gene, which caused a frameshift mutation (Pro236fsTer270) and truncation of the PTF1A protein at codon 270. Detailed postmortem examination in this patient found no sign of pancreatic tissue. Moreover, at the papilla, there was only a ductus choledochus with no sign of endocrine or exocrine pancreatic tissue present surrounding the papilla. Circulating insulin and C peptide levels were measurable, albeit at very low levels, in all affected individuals.
In a male infant, the first child of healthy first-cousin Saudi parents, with pancreatic and cerebellar agenesis (PACA; 609069), Al-Shammari et al. (2011) identified a homozygous deletion (437_460del) in the PTF1A gene, leading to a frameshift and premature termination of the protein (Ala146_Arg154delfsTer115). The mutation is predicted to remove the C-terminal domain as well as the helix-loop-helix domain, rendering the protein inactive.
Adell, T., Gomez-Cuadrado, A., Skoudy, A., Pettengill, O. S., Longnecker, D. S., Real, F. X. Role of the basic helix-loop-helix transcription factor p48 in the differentiation phenotype of exocrine pancreas cancer cells. Cell Growth Diff. 11: 137-147, 2000. [PubMed: 10768861]
Al-Shammari, M., Al-Husain, M., Al-Kharfy, T., Alkuraya, F. S. A novel PTF1A mutation in a patient with severe pancreatic and cerebellar involvement. (Letter) Clin. Genet. 80: 196-198, 2011. [PubMed: 21749365] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01613.x]
Amberger, J. S. Personal Communication. Baltimore, Md. 8/12/2014.
Hoveyda, N., Shield, J. P. H., Garrett, C., Chong, W. K., Beardsall, K., Bentsi-Enchill, E., Mallya, H., Thompson, M. H. Neonatal diabetes mellitus and cerebellar hypoplasia/agenesis: report of a new recessive syndrome. J. Med. Genet. 36: 700-704, 1999. [PubMed: 10507728]
Kawaguchi, Y., Cooper, B., Gannon, M., Ray, M., MacDonald, R. J., Wright, C. V. E. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nature Genet. 32: 128-134, 2002. [PubMed: 12185368] [Full Text: https://doi.org/10.1038/ng959]
Krapp, A., Knofler, M., Frutiger, S., Hughes, G. J., Hagenbuchle, O., Wellauer, P. K. The p48 DNA-binding subunit of transcription factor PTF1 is a new exocrine pancreas-specific basic helix-loop-helix protein. EMBO J. 15: 4317-4329, 1996. [PubMed: 8861960]
Krapp, A., Knofler, M., Ledermann, B., Burki, K., Berney, C., Zoerkler, N., Hagenbuchle, O., Wellauer, P. K. The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes Dev. 12: 3752-3763, 1998. [PubMed: 9851981] [Full Text: https://doi.org/10.1101/gad.12.23.3752]
Masui, T., Long, Q., Beres, T. M., Magnuson, M. A., MacDonald, R. J. Early pancreatic development requires the vertebrate suppressor of hairless (RBPJ) in the PTF1 bHLH complex. Genes Dev. 21: 2629-2643, 2007. [PubMed: 17938243] [Full Text: https://doi.org/10.1101/gad.1575207]
Rose, S. D., Swift, G. H., Peyton, M. J., Hammer, R. E., MacDonald, R. J. The role of PTF1-P48 in pancreatic acinar gene expression. J. Biol. Chem. 276: 44018-44026, 2001. [PubMed: 11562365] [Full Text: https://doi.org/10.1074/jbc.M106264200]
Sellick, G. S., Barker, K. T., Stolte-Dijkstra, I., Fleischmann, C., Coleman, R. J., Garrett, C., Gloyn, A. L., Edghill, E. L., Hattersley, A. T., Wellauer, P. K., Goodwin, G., Houlston, R. S. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nature Genet. 36: 1301-1305, 2004. [PubMed: 15543146] [Full Text: https://doi.org/10.1038/ng1475]
Sellick, G. S., Garrett, C., Houlston, R. S. A novel gene for neonatal diabetes maps to chromosome 10p12.1-p13. Diabetes 52: 2636-2638, 2003. [PubMed: 14514650] [Full Text: https://doi.org/10.2337/diabetes.52.10.2636]
Weedon, M. N., Cebola, I., Patch, A.-M., Flanagan, S. E., De Franco, E., Caswell, R., Rodriguez-Segui, S. A., Shaw-Smith, C., Cho, C. H.-H., Allen, H. L., Houghton, J. A. L., Roth, C. L., and 9 others. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nature Genet. 46: 61-64, 2014. [PubMed: 24212882] [Full Text: https://doi.org/10.1038/ng.2826]