autozygosity.org

Polymicrogyria is a disorder of brain development, in which the cerebral cortical gyri are replaced by numerous excessively small convolutions. Eamonn Sheridan and colleagues have studied individuals with a distinctive combination of polymicrogyria and optic nerve hypoplasia. The disorder was mapped to Chr. 22q11.2 and homozygous mutations demonstrated in TUBA8, an evolutionarily divergent member of the alpha-tubulin gene family. Tubulins and other microtubule-related components are important for correct cortical neuronal migration, being implicated in inherited lissencephalies (smooth brain). The new findings implicate a tubulin of hitherto unknown function in the process of cerebral cortical organization.

The mapping of lethal recessive disorders is sometimes hampered by lack of access to DNA from affected individuals who have died. Colin Johnson, Ian Carr and colleagues have developed an approach to map such disorders by using genetic data from unaffected family members. This strategy, “shadow autozygosity mapping by linkage exclusion” (SAMPLE), allows identification of candidate regions of the genome for further study. For further detail, see the SAMPLE web page.

Yanick Crow (now at the University of Manchester) and colleagues at the Centre for Autozygosity mapping report the identification of SAMHD1 as the fifth gene for Aicardi-Goutières syndrome. This disorder results from constitutive activation of cellular innate immunity. The new finding suggests that SAMHD1, like TREX1 and RNAseH2, prevents activation of innate immunity by endogenous cellular components.

With colleagues at the Institute of Child Health, Eamonn Sheridan, Sally Feather and Angus Dobbie have characterized a new autosomal recessive syndrome of epilepsy, ataxia, deafness, and renal tubulopathy. Their studies show that the condition results from mutation of the potassium channel gene KCNJ10, expressed in the inner ear, brain and kidney. The findings are reported in the New England Journal of Medicine.

Chris Inglehearn and colleagues have used autozygosity mapping to identify a new gene for recessive cone-rod dystrophy. The findings implicate the metalloprotease ADAM9 in this disorder, and led to the demonstration of similar defects in the Adam9 knockout mouse, which now represents a valuable therapeutic model for this form of inherited blindness.