RTTN Mutations Link Primary Cilia Function to Organization of the Human Cerebral Cortex

Abstract

Polymicrogyria is a malformation of the developing cerebral cortex caused by abnormal organization and characterized by many small gyri and fusion of the outer molecular layer. We have identified autosomal-recessive mutations in RTTN, encoding Rotatin, in individuals with bilateral diffuse polymicrogyria from two separate families. Rotatin determines early embryonic axial rotation, as well as anteroposterior and dorsoventral patterning in the mouse. Human Rotatin has recently been identified as a centrosome-associated protein. The Drosophila melanogaster homolog of Rotatin, Ana3, is needed for structural integrity of centrioles and basal bodies and maintenance of sensory neurons. We show that Rotatin colocalizes with the basal bodies at the primary cilium. Cultured fibroblasts from affected individuals have structural abnormalities of the cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B, which are key regulators of cortical patterning and are expressed at the cortical hem, the cortex-organizing center that gives rise to Cajal-Retzius (CR) neurons. Interestingly, we have shown that in mouse embryos, Rotatin colocalizes with CR neurons at the subpial marginal zone. Knockdown experiments in human fibroblasts and neural stem cells confirm a role for RTTN in cilia structure and function. RTTN mutations therefore link aberrant ciliary function to abnormal development and organization of the cortex in human individuals.

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

“…Interestingly, an expression study in RTTN mutant fibroblasts showed a significant deregulation of several genes involved in the SHH and WNT pathways, similarly to what we observed in SUFU mutant cells. 56 Taken together, these observations support the finding that polymicrogyria can be part of the spectrum of brain developmental anomalies associated with deregulation of SHH signaling. Besides SUFU p.Ile406Thr, the two affected siblings in family COR369 also shared the homozygous variant p.Thr716Ser in CDHR1.…”

Primary Cilia in the Developing and Mature Brain

“…(Kheradmand Kia et al, 2012). Humans with mutations show an abnormal cortical organization called polymicrogyria, and structural abnormalities of the cilium.…”

Genetics and mechanisms leading to human cortical malformations

“…associated with autosomal recessive mutations in GPR56, RTTN (rotatin) and PRICKLE1 (Prickle Planar Cell Polarity Protein 1) genes (see Table 5) [176,227,238,239]. The most severe outcomes of PMG occur in children with severe microcephaly (-3 SD or smaller).…”