Severe Phenotype in a Patient With Homozygous 15q21.2 Microdeletion Involving BCL2L10, GNB5, and MYO5C Genes, Resembling Infantile Developmental Disorder With Cardiac Arrhythmias (IDDCA)

Cells use molecular motors, such as myosins, to move, position and segregate their organelles. Class V myosins possess biochemical and structural properties that should make them ideal actin-based cargo transporters. Indeed, studies show that class V myosins function as cargo transporters in yeast, moving a range of organelles, such as the vacuole, peroxisomes and secretory vesicles. There is also increasing evidence in vertebrate cells that class V myosins not only tether organelles to actin but also can serve as short-range, point-to-point organelle transporters, usually following long-range, microtubule-dependent organelle transport.

Array-based comparative genomic hybridization is being increasingly used in patients with learning disability (mental retardation) and congenital anomalies. In this article, we update our previous meta-analysis evaluating the diagnostic and false-positive yields of this technology. An updated systematic review and meta-analysis was conducted investigating patients with learning disability and congenital anomalies in whom conventional cytogenetic analyses have proven negative. Nineteen studies (13,926 patients) were included of which 12 studies (13,464 patients) were published since our previous analysis. The overall diagnostic yield of causal abnormalities was 10% (95% confidence interval: 8-12%). The overall number needed to test to identify an extra causal abnormality was 10 (95% confidence interval: 8-13). The overall false-positive yield of noncausal abnormalities was 7% (95% confidence interval: 5-10%). This updated meta-analysis provides new evidence to support the use of array-based comparative genomic hybridization in investigating patients with learning disability and congenital anomalies in whom conventional cytogenetic tests have proven negative. However, given that this technology also identifies false positives at a similar rate to causal variants, caution in clinical practice should be advised.

RGS (regulator of G protein signaling) proteins containing the G protein gamma-like (GGL) domain (RGS6, RGS7, RGS9, and RGS11) interact with the fifth member of the G protein beta-subunit family, Gbeta5. This interaction is necessary for the stability of both the RGS protein and for Gbeta5. Consistent with this notion, we have found that elevation of RGS9-1 mRNA levels by transgene expression does not increase RGS9-1 protein level in the retina, suggesting that Gbeta5 levels may be limiting. To examine further the interactions of Gbeta5 and the GGL domain-containing RGS proteins, we inactivated the Gbeta5 gene. We found that the levels of GGL domain-containing RGS proteins in retinas and in striatum are eliminated or reduced drastically, whereas the levels of Ggamma2 and RGS4 proteins remain normal in the absence of Gbeta5. The homozygous Gbeta5 knockout (Gbeta5-/-) mice derived from heterozygous knockout mating are runty and exhibit a high preweaning mortality rate. We concluded that complex formation between GGL domain-containing RGS proteins and the Gbeta5 protein is necessary to maintain their mutual stability in vivo. Furthermore, in the absence of Gbeta5 and all four RGS proteins that form protein complexes with Gbeta5, the animals that survive into adulthood are viable and have no gross defects in brain or retinal morphology.