Hamdan Medical Journal (previously the Journal of Medical Sciences)

Table of Contents  

Molecular Genetics of Human Developmental Brain Disorders of the Arabian Gulf Region

Christopher A Walsh
Published in : Journal of Medical Sciences ; Vol 2, No 1 (2009)
DOI : 10.2174/1996327000902010005


Recent work has led to the genetic understanding of an increasingly large number of neurological disorders that affect the nervous system of children, resulting in symptoms such as mental retardation, autistic symptoms, cerebral palsy, or seizures. These conditions are extremely heterogeneous genetically, meaning that large numbers of genes appear to be essential for normal nervous system function, and that mutations in different genes can sometimes cause very similar symptoms. The larger family size, recent population growth, and unique ancestry of populations in the Gulf region provide special opportunities for understanding the causes of childhood neurological isease both here and throughout the world. Here I review some recent developments, and discuss their impact on therapy.

View article in  :   PDF    


Teebi A, Farag T, eds. Genetic disorders among Arab populations, Oxford, Oxford University Press,1997.

Mochida GH, Walsh CA. Genetic basis of developmental malformations of the cerebral cortex. Arch Neurol 2004; 61: 637-40.

Jackson AP, McHale DP, Campbell DA, et al. Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter. Am J Hum Genet 1998; 63: 541-6.

Moynihan L, Jackson AP, Roberts E, et al. A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34. Am J Hum Genet 2000; 66: 724-7.

Pattison L, Crow YJ, Deeble VJ, et al. A Fifth Locus for Primary Autosomal Recessive Microcephaly Maps to Chromosome 1q31. Am J Hum Genet 2000; 67: 1578-80.

Roberts E, Jackson AP, Carradice AC, et al. The second locus for autosomal recessive primary microcephaly (MCPH2) maps to chromosome 19q13.1-13.2. Eur J Hum Genet 1999; 7: 815-20.

Bond J, Roberts E, Mochida GH, et al. ASPM is a major determinant of cerebral cortical size. Nat Genet 2002; 32: 316-20.

Bond J, Scott S, Hampshire DJ, et al. Protein truncating mutations in ASPM cause variable reduction in brain size. Am J Hum Genet 2003; 73: 1170-7.

Roberts E, Hampshire DJ, Pattison L, et al. Autosomal recessive primary microcephaly: ananalysis of locus heterogeneity and phenotypic variation. J Med Genet 2002; 39: 718-21.

Shen J, Eyaid W, Mochida GH, et al. ASPM mutations identified in patients with primary microcephaly and seizures. J Med Genet 2005; 42: 725-9.

Jackson AP, Eastwood H, Bell SM, et al. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 2002; 71: 136-42.

Bond J, Roberts E, Springell K, et al. A centrosomal mechanism involving CDKSRAP2 and CENPJ controls brain size. Nat Genet 2005; 37: 353-5.

Ko1ehmainen J, Norio R, Kivitie-Kallio S, Tahvanainen E, de la Chapelle A, Lehesjoki AE. Refined mapping of the Cohen syndrome gene by linkage disequilibrium. Eur J Hum Genet 1997; 5: 206-13.

Kolehmainen J, Black GC, Saarinen A, et al. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesiclemediated sorting and intracellular protein transport. Am J Hum Genet 2003; 72: 1359-69.

Mochida GH, Rajab A, Eyaid W, et al. Broader geographical spectrum of Cohen syndrome due to COH1 mutations. J Med Genet 2004; 41: e87.

Falk MJ, Feiler HS, Neilson DE, et al. Cohen syndrome in the Ohio Amish. Am J Med Genet A 2004; 128: 23-8.

Hennies HC, Rauch A, Seifert W, et al. Allelic heterogeneity in the COH1 gene explains clinical variability in Cohen syndrome. Am J Hum Genet 2004; 75: 138-45.

Ko1ehmainen J, Wilkinson R, Lehesjoki AE, et al. Delineation of Cohen syndrome following a large-scale genotype-phenotype screen. Am J Hum Genet 2004; 75: 122-7.

Sheen VL, Ganesh VS, Topcu M, et al. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat Genet 2004; 36: 69-76.

Lu J, Tiao G, Folkerth R, Hecht J, Walsh C, Sheen V. Overlapping expression of ARFGEF2 and Filamin A in the neuroependymal lining of the lateral ventricles: insights into the cause ofperiventricular heterotopia. J Comp Neurol

; 494: 476-84.

Rajab A, Mochida GH, Hill A, et al. A novel form of pontocerebellar hypoplasia maps to chromosome 7qll-21. Neurology 2003; 60: 1664- 7.

Pilz DT, Matsumoto N, Minnerath S, et al. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum Mol Genet 1998; 7: 2029-37.

Reiner O, Carrozzo R, Shen Y, et al. Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats. Nature 1993; 364: 717-21.

Gleeson JG, Allen KM, Fox JW, et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 1998; 92: 63-72.

Gleeson JG, Lin PT, Flanagan LA, Walsh CA. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 1999; 23: 257-71.

Gleeson JG, Minnerath SR, Fox JW, et al. Characterization of mutations in the gene doublecortin in patients with double cortex syndrome. Ann Neurol 1999; 45: 146-53.

al-Qudah AA. Clinical patterns of neuronal migrational disorders and parental consanguinity. J Trop Pediatr 1998; 44: 351-4.

Hourihane JO, Bennett CP, Chaudhuri R, Robb SA, Martin ND. A sibship with a neuronal migration defect, cerebellar hypoplasia and congenital lymphedema. Neuropediatrics 1993; 24: 43-6.

al Shawan SA, Bruyn GW, al Deeb SM. Lissencephaly with pontocerebellar hypoplasia. J Child Neurol 1996; 11(3): 241-4.

Hong SE, Shugart YY, Huang DT, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 2000; 26: 93-6.

Fukuyama Y, Ohsawa M. A genetic study of the Fukuyama type congenital muscular dystrophy. Brain Dev. 1984; 6(4): 373-90.

Kobayashi K, Nakahori Y, Miyake M, et al. An ancient retrotransposal insertion causes Fukuyama- type congenital muscular dystrophy. Nature 1998; 394: 388-392.

Santavuori P, Somer H, Sainio K, et al. Muscleeye- brain disease (MEB). Brain Dev 1989; 11: 147-53.

Mochida GH, Walsh CA. Genetic basis of developmental malformations of the cerebral cortex. Arch Neurol. 2004; 61(5): 637-40. Review.

Ranta S, Pihko H, Santavuori P, Tahvanainen E, de la Chapelle A. Muscle-eye-brain disease and Fukuyama type congenital muscular dystrophy are not allelic. Neuromuscul Disord 1995; 5: 221-5.

Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, et al. Mutations in the O-mannosyltrarisferase gene POMT1 give rise to the severe neuronal migration disorder Walker-War burg syndrome. Am J Hum Genet 2002; 71: 1033-43.

van Reeuwijk J, Janssen M, van den Elzen C, et al. POMT2 mutations cause alpha-dystroglycan hypoglycosylation and WalkerWarburg syndrome. J Med Genet 2005; 42: 907-12.

Currier SC, Lee CK, Chang BS, et al. Mutations in POMT1 are found in a minority of patients with Walker-Warburg syndrome. Am J Med Genet A 2005; 133: 53-7.

Piao X, Basel-Vanagaite L, Straussberg R, et al. An autosomal recessive form of bilateral frontoparietal polymicrogyria maps to chromosome 16q12.2-21. Am J Hum Genet 2002; 70: 1028-33.

Piao X, Hill RS, Bodell A, et al. G protein coupled receptor-dependent development of human frontal cortex. Science 2004; 303: 2033- 6.

Chang BS, Piao X, Bodell A, et al. Bilateral frontoparietal polymicrogyria: clinical and radiological features in 10 families with linkage to chromosome 16. Ann Neurol 2003; 53: 596-606.

Dobyns WB, Patton MA, Stratton RF, Mastrobattista JM, Blanton SH, Northrup H. Cobblestone lissencephaly with normal eyes and muscle. Neuropediatrics 1996; 27: 70-5.

Farah S, Sabry MA, Khuraibet A, et al. Lissencephaly associated with cerebellar hypoplasia and myoclonic epilepsy in a Bedouin kindred: a new syndrome? Clin Genet 1997; 51: 326-30.

Joubert M, Eisenring JJ, Andermann F. Familial dysgenesis of the vermis: a syndrome of hyperventilation, abnormal eye movements and retardation. Neurology 1968; 18: 302-3.

Joubert M, Eisenring JJ, Robb JP, Andermann F. Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology 1969; 19: 813-25.

Lambert SR, Kriss A, Gresty M, Benton S, Taylor D. Joubert syndrome. Arch Ophthalmol 1989; 107: 709-13.

Ozonoff S, Williams BJ, Gale S, Miller JN. Autism and autistic behavior in Joubert syndrome. J Child Neurol 1999; 14: 636-41.

Saar K, Al-Gazali L, Sztriha L, et al. Homozygosity mapping in families with Joubert syndrome. identifies a locus on chromosome 9q34.3 and evidence for genetic heterogeneity. Am J Hum Genet 1999; 65: 1666-71.

Bennett CL, Parisi MA, Eckert ML, Huynh HM, Chance PF, Glass IA. Joubert syndrome: a haplotype segregation strategy and exclusion of the zinc finger protein of cerebellum 1 (ZIC1) gene. Am J Med Genet A 2004; 125: 117-24; discussion 117.

Chance PF, Cavalier L, Satran D, Pellegrino JE, Koenig M, Dobyns WB. Clinical nosologic and genetic aspects of Joubert and related syndromes. J Child Neurol 1999; 14: 660-666; discussion 669-72.

Ferland RJ, Eyaid W, Collura RV, et al. Abnormal cerebellar development and axonal decussation due to mutations in AHIl in Joubert syndrome. Nat Genet 2004; 36: 1008-13.

Dixon-Salazar T, Silhavy JL, Marsh SE, et al. Mutations in the AHIl gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet 2004; 75: 979-87.

Parisi MA, Doherty D, Eckert ML, et al. AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome. J Med Genet 2006; 43(4): 334-9.

Kouprina N, Pavlicek A, Mochida GH, et al. Accelerated evolution of the ASPM gene controlling brain size begins prior to human brain expansion. PLoS Biol 2004; 2: E126.

Evans PD, Anderson JR, Vallender EJ, Choi SS, Lahn BT. Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size. Hum Mol Genet 2004a; 13: 1139-45.

Evans PD, Anderson JR, Vallender EJ. et al. Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Hum Mol Genet 2004b; 13: 489-94.

Hill RS, Walsh CA. Molecular insights into human brain evolution. Nature 2005; 437: 64-7.

Allen KM, Gleeson LG., Bagrodia S, et al. PAK3 mutation in nonsyndromic X-linked mental retardation. Nat Genet 1998; 20: 25-30.

Bienvenu T, des Portes V, McDonell N, et al. Missense mutation in PAK3, R67C, causes Xlinked nonspecific mental retardation Am J Med Genet 2000; 93: 294-8.

Bienvenu T, des Portes V, Saint Martin A, et al. Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor. Hum Mol Genet 1998; 7: 1311-5.

D'Adamo P, Menegon A, Lo Nigro C, et al. Mutations in GDIl are responsible for X-linked non-specific mental retardation. Nature Genetics 1998; 19: 134-9.

Basel-Vanagaite L, Attia R, Yahav M, et al. The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive nonsyndromic mental retardation. J Med Genet 2006; 43(3): 203-10.

Add comment 

Home  Editorial Board  Search  Current Issue  Archive Issues  Announcements  Aims & Scope  About the Journal  How to Submit  Contact Us
Find out how to become a part of the HMJ  |   CLICK HERE >>
© Copyright 2012 - 2013 HMJ - HAMDAN Medical Journal. All Rights Reserved         Website Developed By Cedar Solutions INDIA