A neuropathological study of novel RTTN gene mutations causing a familial microcephaly with simplified gyral pattern

Abstract

The present study confirms the involvement of RTTN gene mutations in microcephaly with simplified gyral pattern and describes the observed abnormal neuropathological findings.

Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics

“…Genetic alterations in rotatin, encoded by the RTTN (OMIM #610436) gene, were originally linked to autosomal recessive polymicrogyria in two families, but were later also associated with primary microcephaly and primordial dwarfism in additional families (Kheradmand Kia et al , 2012; Shamseldin et al , 2015; Grandone et al , 2016; Rump et al , 2016; Vora et al , 2017; Cavallin et al , 2018; Chartier et al , 2018; Stouffs et al , 2018; Wambach et al , 2018). Studies in human fibroblasts allocated rotatin to the basal body of the primary cilium, suggesting involvement of the protein in primary ciliogenesis and sonic hedgehog (SHH) signalling (Kheradmand Kia et al , 2012; Wambach et al , 2018).…”

Primary microcephaly, primordial dwarfism, and brachydactyly in adult cases with biallelic skipping of RTTN exon 42

“…This supports the notion that truncating RTTN variants and missense RTTN variants cause distinct forms of cortical malformations (Shamseldin et al, ). Furthermore, our case shows ventricles, brainstem, and cerebellum of normal volumes indicating a relatively intact gross morphology of the brain as compared with the abnormalities associated with missense variants in RTTN (Chartier et al, ; Grandone et al, ; Kheradmand Kia et al, ; Wambach et al, ). In our patients, this implies a defect predominantly in neural proliferation, consistent with deficient formation of full‐length centrioles, whereas a migration defect appears less pronounced.…”

“…In humans, biallelic RTTN variants have been associated with rare cases of polymicrogyria, malformation of the developing cerebral cortex and seizures (Kheradmand Kia et al, ), microcephalic primordial dwarfism (Shamseldin et al, ), and simplified gyri (Chartier et al, ). The human RTTN gene (MIM# 610436) encodes Rotatin, a large centrosomal protein that interacts with the centriolar protein STIL for appropriate assembly of full‐length centrioles (Chen et al, ).…”

Cilia in hereditary cerebral anomalies

“…Interestingly, CC malformations can also be found in association with MCD and primary microcephaly, notably in the case of mutations in WDR62 [Bilgüvar et al., ], ASPM [Passemard et al., ], RTTN [Kheradmand Kia et al., ; Chartier et al., ] or NDE1 [Alkuraya et al., ; Bakircioglu et al., ] all encoding proteins more or less associated to PC dynamics and/or functions. In those cases, PC dysfunctions might affect callosal neuron generation, in addition to callosal axon guidance (see in ‘malformations of cerebral cortical development’).…”