• Seckel syndrome 9

This report describes Seckel syndrome 9 (SCKL9); SCKL9 exhibit autosomal recessive inheritance. The human gene implicated in this disease is TRAIP, which encodes an E3 ubiquitin ligase required to protect genome stability in response to replication stress, acting as a key regulator of interstrand cross-link repair. One of the key phenotypes of Seckel syndrome is microcephaly; it has been observed that most microcephaly disorders are linked to mutations in genes with centrosome and mitotic spindle functions or with DNA damage repair. There is a single Drosophila gene orthologous to TRAIP, Dmel\nopo, for which a number of genetic reagents, including loss-of-function mutations, RNAi targeting constructs, and alleles caused by insertional mutagenesis, have been generated.

The human Hsap\TRAIP gene has been introduced into flies, but has not been characterized in the context of this disease model. Heterologous rescue (functional complementation) has been demonstrated for the Dmel\nopo female sterility phenotype.

Animals homozygous for an amorphic allele of Dmel\nopo survive to adulthood; females are sterile. The mushroom bodies of the adult brain are smaller and contain fewer neurons; no neurodegeneration is observed, which is consistent with human primary microcephaly. Reduced neuron numbers in the mushroom body in nopo mutant animals can be explained by premature loss of neuroblasts; many mushroom body neuronblasts are observed to have prominent chromosome bridges in anaphase, accompanied by polyploidy, aneuploidy, or micronuclei.

[updated Mar. 2024 by FlyBase; FBrf0222196]