@article {161, title = {Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Jul}, pages = {809-13}, abstract = {

Docosahexanoic acid (DHA) is the most abundant omega-3 fatty acid in brain, and, although it is considered essential, deficiency has not been linked to disease. Despite the large mass of DHA in phospholipids, the brain does not synthesize it. DHA is imported across the blood-brain barrier (BBB) through the major facilitator superfamily domain-containing 2a (MFSD2A) protein. MFSD2A transports DHA as well as other fatty acids in the form of lysophosphatidylcholine (LPC). We identify two families displaying MFSD2A mutations in conserved residues. Affected individuals exhibited a lethal microcephaly syndrome linked to inadequate uptake of LPC lipids. The MFSD2A mutations impaired transport activity in a cell-based assay. Moreover, when expressed in mfsd2aa-morphant zebrafish, mutants failed to rescue microcephaly, BBB breakdown and lethality. Our results establish a link between transport of DHA and LPCs by MFSD2A and human brain growth and function, presenting the first evidence of monogenic disease related to transport of DHA in humans.

}, keywords = {Adolescent, Animals, Biological Transport, Blood-Brain Barrier, Brain, Case-Control Studies, Child, Child, Preschool, Consanguinity, Fatty Acids, Omega-3, Female, Genes, Lethal, Genetic Association Studies, HEK293 Cells, Humans, Infant, Male, Mice, Knockout, Microcephaly, Mutation, Missense, Syndrome, Tumor Suppressor Proteins, Zebrafish}, issn = {1546-1718}, doi = {10.1038/ng.3311}, author = {Guemez-Gamboa, Alicia and Nguyen, Long N and Yang, Hongbo and Zaki, Maha S and Kara, Majdi and Ben-Omran, Tawfeg and Akizu, Naiara and Rosti, Rasim Ozgur and Rosti, Basak and Scott, Eric and Schroth, Jana and Copeland, Brett and Vaux, Keith K and Cazenave-Gassiot, Amaury and Quek, Debra Q Y and Wong, Bernice H and Tan, Bryan C and Wenk, Markus R and G{\"u}nel, Murat and Gabriel, Stacey and Chi, Neil C and Silver, David L and Gleeson, Joseph G} } @article {156, title = {Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome.}, journal = {Nat Commun}, volume = {6}, year = {2015}, month = {2015 Jun 16}, pages = {7092}, abstract = {

The short rib polydactyly syndromes (SRPSs) are a heterogeneous group of autosomal recessive, perinatal lethal skeletal disorders characterized primarily by short, horizontal ribs, short limbs and polydactyly. Mutations in several genes affecting intraflagellar transport (IFT) cause SRPS but they do not account for all cases. Here we identify an additional SRPS gene and further unravel the functional basis for IFT. We perform whole-exome sequencing and identify mutations in a new disease-producing gene, cytoplasmic dynein-2 light intermediate chain 1, DYNC2LI1, segregating with disease in three families. Using primary fibroblasts, we show that DYNC2LI1 is essential for dynein-2 complex stability and that mutations in DYNC2LI1 result in variable length, including hyperelongated, cilia, Hedgehog pathway impairment and ciliary IFT accumulations. The findings in this study expand our understanding of SRPS locus heterogeneity and demonstrate the importance of DYNC2LI1 in dynein-2 complex stability, cilium function, Hedgehog regulation and skeletogenesis.

}, keywords = {Biological Transport, Cilia, Cytoplasmic Dyneins, Cytoskeleton, Female, Fibroblasts, Flagella, Hedgehog Proteins, Humans, Male, Mutation, Pedigree, Short Rib-Polydactyly Syndrome}, issn = {2041-1723}, doi = {10.1038/ncomms8092}, author = {Taylor, S Paige and Dantas, Tiago J and Duran, Ivan and Wu, Sulin and Lachman, Ralph S and Nelson, Stanley F and Cohn, Daniel H and Vallee, Richard B and Krakow, Deborah} } @article {268, title = {Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.}, journal = {Science}, volume = {343}, year = {2014}, month = {2014 Jan 31}, pages = {506-511}, abstract = {

Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

}, keywords = {Animals, Axons, Biological Transport, Cohort Studies, Exome, Gene Regulatory Networks, Genetic Association Studies, Humans, Motor Neuron Disease, Mutation, Neurons, Nucleotides, Pyramidal Tracts, Sequence Analysis, DNA, Spastic Paraplegia, Hereditary, Synapses, Transcriptome, Zebrafish}, issn = {1095-9203}, doi = {10.1126/science.1247363}, author = {Novarino, Gaia and Fenstermaker, Ali G and Zaki, Maha S and Hofree, Matan and Silhavy, Jennifer L and Heiberg, Andrew D and Abdellateef, Mostafa and Rosti, Basak and Scott, Eric and Mansour, Lobna and Masri, Amira and Kayserili, H{\"u}lya and Al-Aama, Jumana Y and Abdel-Salam, Ghada M H and Karminejad, Ariana and Kara, Majdi and Kara, Bulent and Bozorgmehri, Bita and Ben-Omran, Tawfeg and Mojahedi, Faezeh and El Din Mahmoud, Iman Gamal and Bouslam, Naima and Bouhouche, Ahmed and Benomar, Ali and Hanein, Sylvain and Raymond, Laure and Forlani, Sylvie and Mascaro, Massimo and Selim, Laila and Shehata, Nabil and Al-Allawi, Nasir and Bindu, P S and Azam, Matloob and G{\"u}nel, Murat and Caglayan, Ahmet and Bilguvar, Kaya and Tolun, Aslihan and Issa, Mahmoud Y and Schroth, Jana and Spencer, Emily G and Rosti, Rasim O and Akizu, Naiara and Vaux, Keith K and Johansen, Anide and Koh, Alice A and Megahed, Hisham and Durr, Alexandra and Brice, Alexis and Stevanin, Giovanni and Gabriel, Stacy B and Ideker, Trey and Gleeson, Joseph G} } @article {305, title = {Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Apr 04}, pages = {632-6}, abstract = {

Biochemical analysis and whole-exome sequencing identified mutations in the Golgi-localized UDP-galactose transporter SLC35A2 that define an undiagnosed X-linked congenital disorder of glycosylation (CDG) in three unrelated families. Each mutation reduced UDP-galactose transport, leading to galactose-deficient glycoproteins. Two affected males were somatic mosaics, suggesting that a wild-type SLC35A2 allele may be required for survival. In infancy, the commonly used biomarker transferrin showed abnormal glycosylation, but its appearance became normal later in childhood, without any corresponding clinical improvement. This may indicate selection against cells carrying the mutant allele. To detect other individuals with such mutations, we suggest transferrin testing in infancy. Here, we report somatic mosaicism in CDG, and our work stresses the importance of combining both genetic and biochemical diagnoses.

}, keywords = {Biological Transport, Case-Control Studies, Child, Child, Preschool, Congenital Disorders of Glycosylation, Exome, Female, Glycosylation, Humans, Male, Monosaccharide Transport Proteins, Mosaicism, Mutation, Spectrometry, Mass, Electrospray Ionization, Transferrin, Uridine Diphosphate Galactose}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.03.012}, author = {Ng, Bobby G and Buckingham, Kati J and Raymond, Kimiyo and Kircher, Martin and Turner, Emily H and He, Miao and Smith, Joshua D and Eroshkin, Alexey and Szybowska, Marta and Losfeld, Marie E and Chong, Jessica X and Kozenko, Mariya and Li, Chumei and Patterson, Marc C and Gilbert, Rodney D and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael J and Freeze, Hudson H} }