MAP1B mutations cause intellectual disability and extensive white matter deficit

Abstract

Discovery of coding variants in genes that confer risk of neurodevelopmental disorders is an important step towards understanding the pathophysiology of these disorders. Whole-genome sequencing of 31,463 Icelanders uncovers a frameshift variant (E712KfsTer10) in microtubule-associated protein 1B (MAP1B) that associates with ID/low IQ in a large pedigree (genome-wide corrected P = 0.022). Additional stop-gain variants in MAP1B (E1032Ter and R1664Ter) validate the association with ID and IQ. Carriers have 24% less white matter (WM) volume (β = −2.1SD, P = 5.1 × 10−8), 47% less corpus callosum (CC) volume (β = −2.4SD, P = 5.5 × 10−10) and lower brain-wide fractional anisotropy (P = 6.7 × 10−4). In summary, we show that loss of MAP1B function affects general cognitive ability through a profound, brain-wide WM deficit with likely disordered or compromised axons.

Unique bioinformatic approach and comprehensive reanalysis improve diagnostic yield of clinical exomes

“…Phenotypic details associated with known diseasecausing genes identified by reanalysis are listed in Table 2. These variants were either recently published, such as CAMK2B (NM_001220.4:c.416C > T, p.(Pro139Leu)) [18], CLTC (NM_004859.3:c.2669C > T, p.(Pro890Leu)) [19], MAP1B (NM_005909.4:c.5368C > T, p.(Arg1790*)) [20], or high impact variants (nonsense, frameshift, hotspot mutation or mutation in functional domains with high conservation) found in disease-causing genes with a clinical presentation that fit the reported patient phenotype, including PPM1D (NM_003620. Overall, the diagnostic yield for reanalyzed negative plus one reclassified CES cases was 32.0% (24/75).…”

Germline AGO2 mutations impair RNA interference and human neurological development

“…Interestingly, we observed enrichment for commonly differentially expressed genes with broad roles in mitosis and cell cycle regulation, including cell division, mitotic nuclear division, sister chromatid cohesion, chromosome segregation, microtubule binding and regulation of cell cycle, to highlight only a few. Notably, the causal link of neurodevelopmental disorders and genes encoding for proteins regulating abovementioned processes have been previously established [40][41][42][43][44][45] . It would be interesting to delineate which of these biological processes are affected in patient primary fibroblasts.…”

Involvement of JNK1 in Neuronal Polarization During Brain Development

“…Notably, no developmental illness has been reported to be caused by genetic mutations of the JNK1 isoform; instead, there is a large body of associative evidence. Surprisingly, this is not the case for its cytosolic substrates, such as MAP1B, MAP2, WRD62, DCX and SCG10, which, in case of impairment, can trigger neurodevelopmental disorders such as microcephaly, lissencephaly, band heterotopia, cortical dysplasia and intellectual disabilities [ 8 , 9 , 10 , 11 , 12 , 13 ].…”