@article {558, title = {MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 12 06}, pages = {1009-1021}, abstract = {

To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but~only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A~gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.10.019}, author = {Dobyns, William B and Aldinger, Kimberly A and Ishak, Gisele E and Mirzaa, Ghayda M and Timms, Andrew E and Grout, Megan E and Dremmen, Marjolein H G and Schot, Rachel and Vandervore, Laura and van Slegtenhorst, Marjon A and Wilke, Martina and Kasteleijn, Esmee and Lee, Arthur S and Barry, Brenda J and Chao, Katherine R and Szcza{\l}uba, Krzysztof and Kobori, Joyce and Hanson-Kahn, Andrea and Bernstein, Jonathan A and Carr, Lucinda and D{\textquoteright}Arco, Felice and Miyana, Kaori and Okazaki, Tetsuya and Saito, Yoshiaki and Sasaki, Masayuki and Das, Soma and Wheeler, Marsha M and Bamshad, Michael J and Nickerson, Deborah A and Engle, Elizabeth C and Verheijen, Frans W and Doherty, Dan and Mancini, Grazia M S} } @article {392, title = {Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Jul 06}, pages = {23-36}, abstract = {

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the "molar tooth sign" on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of families the genetic cause remains unknown. All of the gene products localize in and around the primary cilium, making JS a canonical ciliopathy. Ciliopathies are unified by their overlapping clinical features and underlying mechanisms involving ciliary dysfunction. In this work, we identify biallelic rare, predicted-deleterious ARMC9 variants (stop-gain, missense, splice-site, and single-exon deletion) in 11 individuals with JS from 8 families, accounting for approximately 1\% of the disorder. The associated phenotypes range from isolated neurological involvement to JS with retinal dystrophy, additional brain abnormalities (e.g., heterotopia, Dandy-Walker malformation), pituitary insufficiency, and/or synpolydactyly. We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. Typical ciliopathy phenotypes (curved body shape, retinal dystrophy, coloboma, and decreased cilia) in a CRISPR/Cas9-engineered zebrafish mutant model provide additional support for ARMC9 as a ciliopathy-associated gene. Identifying ARMC9 mutations as a cause of JS takes us one step closer to a full genetic understanding of this important disorder and enables future functional work to define the central biological mechanisms underlying JS and other ciliopathies.

}, keywords = {Abnormalities, Multiple, Animals, Armadillo Domain Proteins, Basal Bodies, Base Sequence, Brain, Cerebellum, Cilia, Ciliopathies, Diagnostic Imaging, Exome, Eye Abnormalities, Genetic Predisposition to Disease, Humans, Kidney Diseases, Cystic, Mutation, Phenotype, Retina, Sequence Analysis, DNA, Up-Regulation, Zebrafish, Zebrafish Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.05.010}, author = {Van De Weghe, Julie C and Rusterholz, Tamara D S and Latour, Brooke and Grout, Megan E and Aldinger, Kimberly A and Shaheen, Ranad and Dempsey, Jennifer C and Maddirevula, Sateesh and Cheng, Yong-Han H and Phelps, Ian G and Gesemann, Matthias and Goel, Himanshu and Birk, Ohad S and Alanzi, Talal and Rawashdeh, Rifaat and Khan, Arif O and Bamshad, Michael J and Nickerson, Deborah A and Neuhauss, Stephan C F and Dobyns, William B and Alkuraya, Fowzan S and Roepman, Ronald and Bachmann-Gagescu, Ruxandra and Doherty, Dan} } @article {228, title = {Mutations in LAMA1 cause cerebellar dysplasia and cysts with and without retinal dystrophy.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Aug 07}, pages = {227-34}, abstract = {

Cerebellar dysplasia with cysts (CDC) is an imaging finding typically seen in combination with cobblestone cortex and congenital muscular dystrophy in individuals with dystroglycanopathies. More recently, CDC was reported in seven children without neuromuscular involvement (Poretti-Boltshauser syndrome). Using a combination of homozygosity mapping and whole-exome sequencing, we identified biallelic mutations in LAMA1 as the cause of CDC in seven affected individuals (from five families) independent from those included in the phenotypic description of Poretti-Boltshauser syndrome. Most of these individuals also have high myopia, and some have retinal dystrophy and patchy increased T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) signal in cortical white matter. In one additional family, we identified two siblings who have truncating LAMA1 mutations in combination with retinal dystrophy and mild cerebellar dysplasia without cysts, indicating that cysts are not an obligate feature associated with loss of LAMA1 function. This work expands the phenotypic spectrum associated with the lamininopathy disorders and highlights the tissue-specific roles played by different laminin-encoding genes.

}, keywords = {Adult, Alleles, Base Sequence, Cerebellar Cortex, Cerebellar Diseases, Child, Child, Preschool, Cysts, Exome, Female, Humans, Laminin, Male, Muscular Dystrophies, Retinal Dystrophies, Sequence Analysis, DNA, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.07.007}, author = {Aldinger, Kimberly A and Mosca, Stephen J and T{\'e}treault, Martine and Dempsey, Jennifer C and Ishak, Gisele E and Hartley, Taila and Phelps, Ian G and Lamont, Ryan E and O{\textquoteright}Day, Diana R and Basel, Donald and Gripp, Karen W and Baker, Laura and Stephan, Mark J and Bernier, Francois P and Boycott, Kym M and Majewski, Jacek and Parboosingh, Jillian S and Innes, A Micheil and Doherty, Dan} }