This report describes Paul-Chao neurodevelopmental syndrome, an intellectual developmental disorder. In most cases characterized to date, this disease exhibits autosomal dominant inheritance associated with de novo missense mutations. The human gene implicated is PPFIA3, which encodes PTPRF interacting protein alpha 3, a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family. There is one high-scoring fly ortholog, Dmel\Liprin-α, for which multiple genetic reagents, including amorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis, have been generated.
Multiple UAS constructs of the human Hsap\PPFIA3 gene, including wild-type Hsap\PPFIA3 and genes carrying missense variants associated with human disease, have been introduced into flies. See the 'Disease-Implicated Variants' table below. Partial heterologous rescue (functional complementation) has been demonstrated for the lethal phenotype of Dmel\Liprin-α loss-of-function mutations.
Ubiquitous overexpression of the Hsap\PPFIA3 variants p.Arg39Cys, p.Ala315Ser, and p.Arg415Trp in flies wild-type for Dmel\Liprin-α results in eclosion defects; p.Arg39Cys is additionally lethal at late pupal stages. Flies that eclose exhibit anatomical defects in leg segments. These phenotypes were not observed with the Hsap\PPFIA3 variants p.Trp546Cys or p.Arg784Trp. Pan-neuronal expression of the Hsap\PPFIA3 variants p.Arg39Cys, p.Ala315Ser, p.Arg415Trp, and p.Arg784Trp exhibit impaired motor coordination in adult flies; p.Arg39Cys, p.Ala315Ser, and p.Arg415Trp also exhibit bang-sensitivity. Pan-neuronal overexpresion of p.Arg39Cys and p.Arg415Trp results in a reduced number of boutons at larval neuromuscular junctions.
Loss of function alleles of Dmel\Liprin-α are lethal at embryonic stages. Lethality is partially rescued by ubiquitous expression of wild-type or mutant Hsap\PPFIA3, with a few flies surviving through adulthood; rescue with wild-type Hsap\PPFIA3 is more robust (FBrf0258489).
[updated May. 2025 by FlyBase; FBrf0222196]
[PAUL-CHAO NEURODEVELOPMENTAL SYNDROME; NEDPACH](https://omim.org/entry/621122)
[PTPRF-INTERACTING PROTEIN ALPHA-3; PPFIA3](https://omim.org/entry/603144)
Paul-Chao neurodevelopmental syndrome (NEDPACH) is an autosomal dominant disorder characterized by global developmental delay, delayed walking, variably impaired intellectual development, and poor or absent speech. Affected individuals may have hypotonia, seizures, dysmorphic facial features, and behavioral abnormalities, including autism and ADHD. Most individuals attend special schools. The phenotype is highly variable and is likely influenced by genetic background and complicating medical morbidities (Paul et al., 2024; pubmed:38181735). [from MIM:621122; 2025.05.17]
A cohort of 20 individuals from 18 families exhibit a neurodevelopmental phenotype associated with PPFIA3 variants, presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy (Paul, et al., 2024 pubmed:38181735; FBrf0258489).
Paul-Chao neurodevelopmental syndrome (NEDPACH) is caused by heterozygous mutation in the PPFIA3 gene on chromosome 19q13. [from MIM:621122; 2025.05.17]
Heterozygous or compound heterozygous variants identifed in PPFIA3 include missense, frameshift deletion, exonic deletion, or consensus splice site variants (Paul, et al., 2024 pubmed:38181735; FBrf0258489).
PPFIA3, or liprin-alpha-3, belongs to the liprin-alpha gene family and encodes a protein that plays a role in the organization and function of synapses, particularly at the presynaptic active domain (Serra-Pages et al., 1998; pubmed:9624153; summary by Paul et al., 2024; pubmed:38181735). [from MIM:603144; 2025.05.17]
PPFIA3 encodes PTPRF interacting protein alpha 3, a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family. Liprins interact with members of LAR family of transmembrane protein tyrosine phosphatases, which are known to be important for axon guidance and mammary gland development. Liprin family protein has been shown to localize phosphatase LAR to cell focal adhesions and may be involved in the molecular organization of presynaptic active zones. [provided by RefSeq, Jul 2008]
Many to one (many human to 1 Drosophila); PPFIA3 has one high-scoring Drosophila ortholog, Liprin-α.
High-scoring ortholog of human PPFIA1, PPFIA2, PPFIA3, PPFIA4.
