The reference OMIM entry for this protein is 607629

Anterior pharynx defective 1, c. elegans, homolog of, a; aph1a

DESCRIPTION

APH1 is a multipass transmembrane protein that interacts with presenilin (see PSEN1; 104311) and nicastrin (APH2; 605254) as a functional component of the gamma-secretase complex. The gamma-secretase complex is required for the intramembrane proteolysis of a number of membrane proteins, including the amyloid-beta precursor protein (APP; 104760) and Notch (190198).

CLONING

By searching a sequence database for homologs of the C. elegans Aph1 gene, which carries mutations in the anterior pharynx-defective phenotype, Goutte et al. (2002) identified human APH1A and APH1B (607630). The predicted 251- and 257-amino acid APH1A and APH1B proteins share 33% and 34% identity with C. elegans Aph1, respectively. APH1A had been identified as CGI-78 by Lai et al. (2000). Francis et al. (2002) identified 2 presenilin enhancers in C. elegans, Aph1 and Pen2 (607632). By searching sequence databases, they identified APH1A and APH1B as human homologs of Aph1, and they identified homologs in mouse, zebrafish, and Drosophila. The predicted 247-amino acid APH1A protein contains 7 transmembrane domains and shares 59% identity with APH1B and 99% identity with mouse Aph1a. Francis et al. (2002) also identified an APH1A alternative splice form in human and mouse that results in a 265-amino acid protein with a different C terminus. Lee et al. (2002) isolated APH1A and APH1B cDNAs from a glioblastoma cDNA library. By Western blot analysis, they showed that APH1A has a relative molecular mass of approximately 30 kD.

GENE FUNCTION

Goutte et al. (2002) showed that C. elegans embryos with mutations in the Aph1 gene lacked the anterior pharynx but could develop a relatively normal posterior pharynx, a phenotype similar to that associated with mutations in Notch pathway components. After analyzing Aph1 mutant embryos, they concluded that Aph1 and presenilins are required for cell surface localization of the Notch component Aph2 (nicastrin). By analyzing C. elegans mutant phenotypes, Francis et al. (2002) determined that Aph1 and Pen2 were required for Glp1/Notch-mediated signaling, both in embryonic patterning and in postembryonic germline proliferation. They observed that the human APH1 and PEN2 genes partially rescued the C. elegans mutant phenotypes, demonstrating conserved functions. Human APH1 and PEN2 had to be provided together to rescue the mutant phenotypes, and inclusion of PSEN1 improved rescue. Francis et al. (2002) concluded that APH1 and PEN2 cooperate closely in the same process to promote presenilin activity. Using RNA-mediated interference assays to inactivate Aph1, Pen2, or nicastrin in cultured Drosophila cells, Francis et al. (2002) observed reduction in gamma-secretase cleavage of beta-APP and Notch substrates and reduction in the levels of processed presenilin. They concluded that APH1 and PEN2 are required for Notch pathway signaling, gamma-secretase cleavage of beta-APP, and presenilin protein accumulation. In a commentary, Goutte (2002) discussed the contribution of Francis et al. (2002) to current understanding of how presenilins mediate the gamma-secretase cleavage of Notch transmembrane receptors and transmembrane beta-APP. Using coimmunoprecipitation and nickel affinity pull-down approaches, Lee et al. (2002) showed that mammalian APH1A and APH1B physically associated with nicastrin and presenilin heterodimers in vivo. Inactivation of endogenous APH1 using small interfering RNAs resulted in decreas ... More on the omim web site

Subscribe to this protein entry history

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 607629 was added.

May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).