Browsing by Subject "Gait disorders Genetic aspects."

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Open Access
Identification of ATP8A2 gene mutation in a consaguineous family segregating cerebellar atrophy and quadrupedal gait
(2012) Onat, Onur Emre
Cerebellar ataxia, mental retardation, and dysequilibrium syndrome is a rare and heterogeneous neurodevelopmental disorder characterized by cerebellar atrophy, dysarthric speech, and quadrupedal locomotion. Here, a consanguineous family with four affected individuals which suggest an autosomal recessive inheritance was investigated. Homozygosity mapping analysis using high-resolution genotyping arrays in two affected individuals revealed four shared homozygous regions on 13q12, 19p13.3, 19q13.2, and 20q12. Target enrichment and next-generation sequencing of these regions in an affected individual was uncovered 11 novel protein altering variants which were filtered against dbSNP132 and 1000 genomes databases. Further population filtering using personal genome databases and previous exome sequencing datasets, segregation analysis, geographically-matched population screening, and prediction approaches revealed a novel missense mutation, p.I376M, in ATP8A2 segregated with the phenotype in the family. The mutation resides in a highly conserved C-terminal transmembrane region of E1-E2 ATPase domain. ATP8A2 is mainly expressed in brain, in particular with the highest levels at cerebellum which is a crucial organ for motor coordination. Mice deficient with Atp8a2 revealed impaired axonal transport in the motor neurons associated with severe cerebellar ataxia and body tremors. Recently, an unrelated individual with a de novo t(10;13) balanced translocation whose one of the ATP8A2 allele was disrupted has been identified. This patient shares similar neurological phenotypes including severe mental retardation and hypotonia. These findings suggest a role for ATP8A2 in the neurodevelopment, especially in the development of cerebro-cerebellar structures required for posture and gait in humans.
Open Access
Identification of very low density lipoprotein receptor (VLDLR) mutations in cerebellar hypoplasia and quadrupedal locomotion (unertan syndrome) in humans
(2008) Çağlayan, Şafak
Cerebellar hypoplasia and quadrupedal locomotion in humans, also known as Unertan syndrome, is a severe neurodevelopmental condition accompanied by dysarthria and impaired cognitive skills. The molecular underpinnings of development of the brain structures required for bipedal gait in humans can be established through identification of the gene(s) associated with this disorder. Four consanguineous families from Turkey exhibiting this autosomal recessive trait were studied. In two families (A and D), affected individuals shared homozygosity in a critical 1.032-Mb region in chromosome 9p24. Sequence analysis linked the disease to two distinct mutations in the very low density lipoprotein receptor (VLDLR) gene; the nonsense change R257X in family A and the single nucleotide deletion leading to frameshift I780TfsX3 in family D. VLDL receptor is a co-receptor of reelin molecule. Reelin signaling pathway is involved in neuronal migration and lamination to form brain cortices during embryonic development. Mutant VLDL receptors are truncated proteins that cannot be inserted into the membrane. Homozygosity mapping linked the disease locus in family B to chromosome 17p13. Family C does not share homozygosity in neither of the loci.
Open Access
Quadrupedal gait in humans : identification and partial characterization of a novel gene WD repeat domain 81 (WDR81)
(2011) Gülsüner, Süleyman İsmail
Identi cation of disease genes responsible for cerebellar phenotypes provides mechanistic insights into the development of cerebellum. Neural pathways involved in bipedal gait in humans is not completely understood. Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) is a rare neurodevelopmental disorder accompanied by quadrupedal gait, dysarthric speech and cerebellar hypoplasia. A large consanguineous family exhibiting this rare disorder was investigated in this study. Disease locus was mapped to a 7.1 Mb region on chromosome 17p by genetic analysis. Targeted capture and massively parallel DNA sequencing using the DNA of three a ected and two carrier individuals enabled the identi cation of a novel variant, p.P856L, in a predicted transcript of WD repeat domain 81 gene (WDR81). Several exclusion lters including segregation analysis, identi cation of rare polymorphisms, extended pedigree screen and bioinformatics evaluation was performed. Expression analysis revealed highest levels of transcripts in cerebellum and corpus callosum. In mouse brain Wdr81 RNA was observed in cerebellum, especially in Purkinje cell layer. The major structural abnormalities of the patients were atrophy of superior, middle and inferior cerebellar peduncles and corpus callosum. These ndings are compatible with the expression pattern of the gene. Analysis of the developing mouse brain revealed that, the expression pattern of the gene was correlated with those involved in neuronal di erentiation. This study was one of the rst examples of the utility of next generation sequencing in discovery of genes associated with Mendelian phenotypes.