Research
  In our effort to identify genes important for brain development, we compare the DNA sequences of individuals with disorders of brain development to their family members and other research cases. Genetic differences that are found are studied to determine if they are truly disease-causing and to better understand their effect.
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  Genes Identified

AHI1
AKT3
ARFGEF2
ASPM
CDK5RAP2
CENPJ
CHMP1A
DCX
FLNA
GPR56
GTDC2
JAM3
NDE1
PAK3
PNKP
POMT1
RELN
TRAPPC9
WDR62
ZNF335


AHI1 ~ Abelson helper integration site gene ~ 6q23.3
We identified a locus on chromosome 6q23.2-q23.3, called JBTS3, to be associated with Joubert syndrome in 5 families from Saudi Arabia and Turkey. In these families, 3 independent mutations were found in AHI1, the first gene to be associated with Joubert syndrome, an autosomal recessive, multisystem disorder that includes absence or underdevelopment of the cerebellar vermis.  Ferland et al., Nature Genetics 36 (9): 1008-13, 2004.




AKT3 ~ RAC-gamma serine/threonine-protein kinase ~ 1q43-q44
We compared surgically resected brain tissue to blood samples from 8 individuals with hemimegalencephaly. An activating AKT3 mutation in one individual and two cases of trisomy 1q, encompassing AKT3, were found in brain tissue but not in blood samples, supporting a role for somatic mutations in neurologic disease. Poduri et al., Neuron 74(1):41-8, 2012.




ARFGEF2 ~ ADP-ribosylation factor guanine nucleotide-exchange factor-2 gene ~ 20q13.13

We studied 2 Turkish families with autosomal recessive periventricular heterotopia and microcephaly, and described genetic linkage between them at a single locus on chromosome 20q11.21-13.2. This led to the identification of independent mutations in each family in the ARFGEF2 gene.  Sheen et al., Neurology 60, 1108-1112, 2003. Sheen et al., Nature Genetics 36 (1): 69-76, 2004.




ASPM ~ Abnormal spindle homolog, microcephaly associated gene ~ 1q31.3

In collaboration with Dr. Woods' laboratory at the University of Leeds in the UK, we found ASPM to be the gene within the previously identified MCPH5 locus associated with autosomal recessive primary microcephaly. Positional cloning was applied to 24 consanguineous families that included 61 affected individuals and several homozygous mutations in ASPM were described.  Bond et al., Nature Genetics 32 (2): 316-320, 2002.




CDK5RAP2 ~ Cyclin dependant kinase 5 regulatory subunit associated protein 2 gene ~ 9q33.2

In collaboration with Dr. Woods' laboratory at the University of Leeds in the UK, CDK5RAP2 was found to be the gene within the previously identified MCPH3 locus associated with autosomal recessive primary microcephaly. Positional cloning was applied to 2 consanguineous families and a homozygous mutation in CDK5RAP2 was described in each.  Bond et al., Nature Genetics 37 (4): 353-5, 2005.




CENPJ ~ Centromere protein J gene ~ 13q12.12

In collaboration with Dr. Woods' laboratory at the University of Leeds in the UK, CENPJ was found to be the gene within the previously identified MCPH6 locus associated with autosomal recessive primary microcephaly. Positional cloning was applied to 3 consanguineous families and a homozygous mutation in CENPJ was described in each.  Bond et al., Nature Genetics 37 (4): 353-5, 2005.




CHMP1A ~ Charged multivesicular body protein 1a ~ 16q24.3
We studied 3 families with underdevelopment of the cerebellum, pons, and cerebral cortex, and identified a homozygous region on chromosome 16q in all affected individuals. Sequencing in the region revealed homozygous mutations in the CHMP1A gene. Mochida et al., Nat Genet 44(11):1260-4, 2012.




DCX ~ Doublecortin gene ~ Xq23

We studied 4 families with multiple individuals with double cortex/X-linked lissencephaly alongside 3 individuals with double cortex syndrome that did not have a family history of the condition. Linkage of these families to Xq21-24 and a translocation in an affected female [t(X;2)(q22;p21)] led to the identification of independent mutations in the DCX gene. Gleeson et al., Cell 92 (1): 63-72, 1998.




FLNA ~ Filamin A gene ~ Xq28

We mapped the gene associated with X-linked dominant periventricular heterotopia to chromosome Xq28 in 11 females, 8 from 2 families with multiple affected individuals and 3 from families with no other affected individuals. Refined mapping and candidate gene sequencing identified multiple independent mutations in FLNA (previously called filamin1 or FLN 1). Ekşioĝlu et al., Neuron 16(1):77-87, 1996. Fox et al., Neuron 21(6): 315-25, 1998.




GPR56 ~ G protein-coupled receptor 56 gene ~ 16q21

We studied 2 consanguineous Palestinian families with 5 individuals affected with autosomal recessive bilateral frontoparietal polymicrogyria (BFPP) and described genetic linkage between them at chromosome 16q12.2.-21. Subsequently, analysis of 22 individuals with BFPP from 12 families identified 8 independent mutations in the GPR56 gene. Piao et al., Am J Hum Genet 70: 1028-1033, 2002.




GTDC2 ~ Glycosyltransferase-like domain-containing protein 2 ~ 3p22.1
We studied a cohort of consanguineous families, each with at least one individual affected with Walker-Warburg syndrome. Whole-genome SNP arrays identified regions of homozygosity, and subsequent whole-exome sequencing identified mutations in the GTDC2 gene in 3 families.  Manzini et al., Am J Hum Genet 91(3):541-7, 2012.




JAM3 ~ Junctional adhesion molecule 3 gene ~ 11q25

We studied a large consanguineous family from the United Arab Emirates with an autosomal recessive condition characterized by hemorrhagic destruction of the brain, subependymal calcification and congenital cataracts. Homozygosity mapping and candidate gene sequencing led to the identification of a homozygous mutation in the JAM3 gene. Mochida et al., Am J Hum Genet 87, 2010.




NDE1 ~ nuclear distribution protein nudE homolog 1 ~ 16p13.11
In collaboration with Dr. Alkuraya's lab at King Faisal Specialist Hospital and Research Center, we studied 2 consanguineous families from Saudi Arabia with autosomal recessive severe microcephaly and simplified gyral pattern. Homozygosity mapping and candidate gene sequencing led to the identification of mutations in the NDE1 gene. Alkuraya et al., Am J Hum Genet 88(5):536-47, 2011.




PAK3 ~ p21 Protein (Cdc42/Rac)-activated kinase 3 gene ~ Xq23

In collaboration with researchers at the Institut National de la Sante et de la Recherche Medicale in France, a mutation in the PAK3 gene was identified to cause X-linked non-syndromic intellectual disability.Bienvenu et al., Am J Med Genet 93 (4): 294-8, 2000.




PNKP ~ Polynucleotide kinase 3'-phosphatase gene ~ 19q13.33

We studied 7 families from Palestine, Saudi Arabia, Turkey and the USA with autosomal recessive microcephaly, early onset intractable seizures and developmental delay. Genome-wide linkage data from 3 consanguineous families and subsequent gene sequencing led to the identification of several independent mutations in the PNKP gene. Shen, et al., Nature Genetics 42(3): 245-9, 2010.




POMT1 ~ Protein-O-mannosyltransferase 1 gene ~ 9q34.13

In collaboration with Dr. Brunner's laboratory in the Netherlands, a new gene associated with the heterogeneous autosomal recessive condition, Walker-Warburg syndrome, was found. Homozygosity mapping in several consanguineous families and subsequent candidate gene sequencing led to the identification of 6 independent mutations in POMT1.Currier et al., Am J Med Genet A 133A (1): 53-57, 2005.




RELN ~ Reelin gene ~ 7q22.1

Through the study of 2 consanguineous families from Saudi Arabia and England, mutations in the RELN gene were found in our laboratory to be associated with autosomal recessive lissencephaly with cerebellar hypoplasia. Candidate gene sequencing led to the identification of 2 independent homozygous mutations in these families. Hong et al., Nature Genetics 26 (1): 93-96, 2000.




TRAPPC9 ~ Trafficking protein particle complex 9 gene ~ 8q24.3

We studied a consanguineous Israeli Arab family with 3 individuals with moderate to severe intellectual disability and variable postnatal microcephaly. Homozygosity mapping and candidate gene sequencing within the region of linkage revealed a homozygous mutation in TRAPPC9. Mochida et al., Am J Hum Genet 85(6): 897-902, 2009.




WDR62 ~ WD repeat-containing protein 62 gene ~ 19q13.12

Six families with microcephaly and abnormal cortical development were found to have mutations in the WDR62 gene. Homozygosity mapping of 2 consanguineous families followed by high-throughput sequence analysis of almost 150 genes led to the identification of mutations in the WDR62 gene. Yu et al., Nat Genet. 2010 Nov;42(11):1015-20.




ZNF335 ~ Zinc finger protein 335 ~ 20q13.12
We studied a large consanguineous Arab Israeli family with 7 individuals affected with an autosomal recessive condition causing severe microcephaly, small body size and early death. Homozygosity mapping, followed by candidate gene sequencing, identified a homozygous, non-synonymous mutation in the ZNF335 gene. Yang et al., Cell 151(5):1097-1112, 2012.



 
 
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