This report describes pontocerebellar hypoplasia, type 1B (PHC1B), a severe neurologic disorder; PHC1B exhibits autosomal recessive inheritance. The human gene implicated in this disease is EXOSC3, a component of the human exosome, which plays a role in numerous RNA processing and degradation activities. There is a single orthologous gene in Drosophila, Rrp40, for which missense mutations, RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated
A UAS construct of the wild-type human Hsap\EXOSC3 gene has been introduced into flies. Partial heterologous rescue (functional complementation) is observed for alleles of Dmel\Rrp40 analogous to variants implicated in PHC1B.
Effects of Rrp40 loss of function have been assessed using RNAi and various different drivers: global, pan-neuronal, glial, and muscle-specific. With drivers expressed starting in embryogenesis lethality is observed prior to eclosion. RNAi targeted to later stages reveals ongoing requirement for Rrp40 function in neurons and the brain.
Missense mutations analogous to variants implicated in PHC1B have been introduced into the Drosophila Rrp40 gene. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G11A in the fly Rrp40 (corresponds to G31A in the human EXOSC3 gene); D87A in the fly Rrp40 (corresponds to D132A in the human EXOSC3 gene). In homozygous or hemizygous mutant animals viability is significantly reduced; surviving adults exhibit morphological defects, progressive locomotor defects, and abnormal brain morphology. Results support the hypothesis that both variants are loss-of-function mutations.
[updated Sep. 2020 by FlyBase; FBrf0222196]
Multiple subtypes of pontocerebellar hypoplasia have been described. All forms of this condition are characterized by impaired brain development, delayed development overall, problems with movement, and intellectual disability. The brain abnormalities are usually present at birth, and in some cases they can be detected before birth. Many children with pontocerebellar hypoplasia live only into infancy or childhood, although some affected individuals have lived into adulthood. [MedlinePlus, Pontocerebellar hypoplasia; 2022.04.16]
Pontocerebellar hypoplasia (PCH) refers to a group of severe neurodegenerative disorders affecting growth and function of the brainstem and cerebellum, resulting in abnormally small cerebellum and brainstem. [from MIM:607596; 2022.04.16]
[PONTOCEREBELLAR HYPOPLASIA, TYPE 1B; PCH1B](https://omim.org/entry/614678)
[EXOSOME COMPONENT 3; EXOSC3](https://omim.org/entry/606489)
Pontocerebellar hypoplasia type 1B is a severe autosomal recessive neurologic disorder characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There is diffuse muscle weakness, progressive microcephaly, global developmental delay, and brainstem involvement (summary by Wan et al., 2012; pubmed:22544365). PCH1B can be divided into mild, moderate, and severe subgroups that vary in age at onset, progression, clinical and neuroradiologic severity, and survival (summary by Halevy et al., 2014; pubmed:25149867). [from MIM:614678; 2020.09.07]
Pontocerebellar hypoplasia type 1B (PCH1B) is caused by homozygous or compound heterozygous mutation in the EXOSC3 gene. [from MIM:614678; 2020.09.07]
EXOSC3 (Exosome Component 3) encodes a non-catalytic component of the human exosome, a complex with 3'-5' exoribonuclease activity that plays a role in numerous RNA processing and degradation activities in both the nucleus and the cytoplasm. The catalytic inactive RNA exosome core complex of 9 subunits is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. [Gene Cards, EXOSC3; 2020.09.07]
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human EXOSC3 (1 Drosophila to 1 human). Dmel\Rrp40 shares 40% identity and 63% similarity with the human gene.
