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. 2018 Aug 27;9(1):3456.
doi: 10.1038/s41467-018-05595-6.

MAP1B Mutations Cause Intellectual Disability and Extensive White Matter Deficit

Free PMC article

MAP1B Mutations Cause Intellectual Disability and Extensive White Matter Deficit

G Bragi Walters et al. Nat Commun. .
Free PMC article


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.

Conflict of interest statement

G.B.W., O.G., G.S., A.B.A., G.A.J., S.S., A.F.G., M.I.M., U.U., A.L.L., A.d.J., A.Si., A.s.J., A.Sk., M.S.N., P.S., M.F., A.I., G.L.N., M.Z., D.F.G., M.O.U., H.S. and K.S. are employees of deCODE genetics/Amgen. The remaining authors declare no competing interests.


Fig. 1
Fig. 1
Pedigree plots for MAP1B LoF carrier families. a Family 1 (FAM1)—E712KfsTer10 (c.2133delG), b Family 2 (FAM2)—E1032Ter (c.3094 G > T) and c Family 3 (FAM3)—R1664Ter (c.4990 C > T). Squares are male, circles are female, diamonds are where gender is withheld, unfilled are unaffected, filled with black are intellectual disability affected, half black and white are individuals without a clinical diagnosis but an IQ below 70, blue are Autism spectrum disorder affected and yellow and white squares within the pedigree symbol indicates where it is most likely the initial MAP1B LoF mutation event occurred. Below each icon is the subjects: alias; MAP1B LoF variant genotype; Full-scale IQ (Verbal IQ/Performance IQ) from WASIIS or WPPSI-R (FAM1-B1,-B3,-C1,-C2,-D1,-D2,-D3; FAM2-H1,-H2,-J2; FAM3-K1,-K2,-L1 or FAM1-D5,-E1, respectively), or only Full-scale IQ reported from WISC-IV (FAM1-D4, FAM2-J1,-J3 and FAM3-M1), and corpus callosum (CC) volume (all individuals with structural MRI also have DTI except FAM1-C1). Refer to Supplementary Figure 2 for a description of how the de novo event carriers were identified
Fig. 2
Fig. 2
CC and WM volume differences in MAP1B LoF carriers compared with controls. a The colour scales refer to regions that are smaller (blue) or larger (red/yellow) in MAP1B LoF carriers (n = 10) compared with controls (n = 949). See Tables 3 and 4 for details. The four brain aspects in the left of the figure are from top left and clockwise: left hemisphere (LH) lateral surface, right hemisphere (RH) lateral surface, RH medial surface and LH medial surface. The middle image is an axial slice with the front of the brain at the top of the figure and demonstrates the ubiquitous nature of the WM and GM effects; R is right and L is left. The image on the right is a glass brain highlighting the significant reduction in WM in the corpus callosum. b Unadjusted corpus callosum and cerebral WM volumes plotted against intracranial volume (ICV) from FreeSurfer (in mm3) for MAP1B LoF carriers (blue) compared with controls (grey). Relative to the linear regression (diagonal line) the MAP1B LoF carriers have smaller CC and cerebral WM volumes than would be predicted from their ICV
Fig. 3
Fig. 3
Diffusion (TBSS) data mapping from MAP1B LoF carriers compared with controls. Rows one, two, and three show, respectively, axial, coronal, and sagittal aspects of brain (MNI coordinates: 1, −13, 19) where heat map (red/yellow) intensity represents a significant change in fractional anisotropy (FA). a We compared MAP1B LoF carriers (n = 9) with three control groups (column i: normal range controls (n = 181), column ii: controls with small CC volume (β < −1.5 SD, n = 15), and column iii: controls with small WM volume (β < −1.5 SD, n = 10)) and found the carriers to have significantly lower brain-wide FA compared with all three control groups. b To determine whether a smaller CC volume generally leads to a decrease in FA, we compared the, column (i) 15 controls with smaller CC with 166 normal range controls and, column (ii) the ten controls with smaller WM with 160 normal range controls and found a reduction in FA only in the densest part of the CC. Family wise error (FWE) corrected significance threshold of 0.05
Fig. 4
Fig. 4
Western blot of antibody binding to wild-type and truncated MAP1B proteins. a An image, from the Odyssey system, where the colour coded infrared fluorescent signals from the 700 nm channel (V5 antibody signal—blue) and the 800 nm channel (MAP1B antibody signal—green) are taken from the same blot; cyan indicates where both antibody signals overlap. See Supplementary Figure 7 for the individual V5 and MAP1B antibody signal greyscale pictures. b A schematic diagram of what each band on the western blot represents in the context of protein size (heavy chain (HC), light chain 1 (LC1) and truncated proteins). c A schematic diagram of truncated MAP1B and an indication of whether the anti-V5 or anti-MAP1B antibodies bind the protein product. The wild-type HC is only recognised by the anti-MAP1B antibody (green), and the wild-type LC1 is only recognised by the anti-V5 antibody (blue), while both anti-MAP1B and anti-V5 antibodies bind to all three truncated protein products as they contain both the MAP1B (amino acids 6-31) and V5 tags (cyan bands in b). The red X indicates that the LC1 is not produced as a consequence of the MAP1B truncation. AB actin-binding domain, MTA microtubule assembly helping site, putative, MTB microtubule-binding domain

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