Showing papers by "Kaya Bilguvar published in 2013"

Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO

Abstract: We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7 , a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4 , a transcription factor known for its role in inducing pluripotency, or with AKT1 E17K , a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non- NF2 mutant meningiomas. These non- NF2 meningiomas were clinically distinctive—nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.

Abstract: Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific de-ubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Through homozygosity mapping of the affected individuals followed by whole-exome sequencing of the index case, we identified a previously undescribed homozygous missense mutation within the ubiquitin binding domain of UCHL1 (UCHL1GLU7ALA), shared by all affected subjects. As demonstrated by isothermal titration calorimetry, purified UCHL1GLU7ALA, compared with WT, exhibited at least sevenfold reduced affinity for ubiquitin. In vitro, the mutation led to a near complete loss of UCHL1 hydrolase activity. The GLU7ALA variant is predicted to interfere with the substrate binding by restricting the proper positioning of the substrate for tunneling underneath the cross-over loop spanning the catalytic cleft of UCHL1. This interference with substrate binding, combined with near complete loss of hydrolase activity, resulted in a >100-fold reduction in the efficiency of UCHL1GLU7ALA relative to WT. These findings demonstrate a broad requirement of UCHL1 in the maintenance of the nervous system.

Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion.

Abstract: Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebro-cerebellar structures required for posture and gait in humans.

Mutations in LAMB1 Cause Cobblestone Brain Malformation without Muscular or Ocular Abnormalities

Abstract: Cobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation.

Whole-exome sequencing identified a patient with TMCO1 defect syndrome and expands the phenotic spectrum

Abstract: To the Editor : In 2010, Xin et al. described a new autosomal-recessive syndrome which includes mental retardation, dysmorphism, skeletal and neurological findings in an Amish family secondary to mutations in the Transmembrane and coiled-coil domain-containing protein 1 (TMCO1 ) gene (1). Here, we report the first non-Amish case with a TMCO1 mutation. Our index case is a 7-year-old boy, SA (Fig. 1a, IV-3), who presented to paediatric neurology clinic due to delayed development (Fig. S1, Supporting information). His parents were first-cousins (Fig. 1a) and he was born at 37 weeks gestation with a head circumference of 38 cm (90%). SA was hypotonic at birth with feeding difficulties and was diagnosed with hypothyroidism. He later was found to have significant delays with the neurodevelopmental milestones, being unable to walk and with minimal speech. His family noted him to be anxious and showing selfmutilating behavior like chewing his fingers. When he was examined at the referring paediatric neurology clinic at 7 years of age, his head circumference was 53 cm (75–90%), his weight was 17 kg, (<5%) and height 113 cm (5%). His general physical examination was remarkable for several dysmorphic features including short neck, low hairline, low set ears, synophrys, hypertelorism, antevert nares, high-arched palate, prognatism, hyperextensbile fingers, pectus carinatum, scoliosis and genu varus. On neurological examination, he was awake but unable to speak except a few basic words. He was unable to walk, feed himself or perform activities of daily living. There were no abnormalities in routine laboratory tests, including complete blood count (CBC), blood chemistries, urine test, and plasma aminoacid levels. Chest X-ray was remarkable for rib and scapula abnormalities. On brain magnetic resonance imaging, dysgenesis of the corpus callosum and cerebellar herniation were detected (Fig. S2). In order to identify the disease causing variant, we performed homozygosity mapping followed by whole exome sequencing using Nimblegen solid phase arrays (Roche NimbleGen, Inc., Madison, WI) and the Illumina HiSeq 2000 (Illumina, Inc., San Diego, CA). We achieved a mean coverage of 30.5×, and 91.47% of all targeted bases were covered more than four times, sufficient to identify novel homozygous variants with high specificity (2) (Tables S1 and S2). We a)

Spondyloepimetaphyseal dysplasia Pakistani type: expansion of the phenotype.

Abstract: Spondyloepimetaphyseal dysplasia (SEMD), Pakistani type, is a skeletal dysplasia characterized by platyspondyly, delayed epiphyseal ossification, mild metaphyseal abnormalities, short stature, and short and bowed legs, and is caused by mutations in PAPSS2. In a single Turkish patient also hyperandrogenism was reported. We describe five patients from a Turkish family with SEMD Pakistani type with homozygosity for a nonsense mutation (p.R329X) leading to a stop codon in PAPSS2. Plasma levels of dehydroepiandrosterone (DHEA) and androstenedione were normal, but DHEA sulfate levels were low in four of the patients. Two patients and a mother had history of pubertal hyperandrogenism. Testosterone level was mildly elevated in one of the female patients, and insulin resistance was not detected in any of the patients. The patients also had precocious costal calcification, small iliac bones, short femoral necks, coxa vara, short halluces and fused vertebral bodies, none of which has been reported previously in this entity. (c) 2013 Wiley Periodicals, Inc.

A new patient with Andermann syndrome: an underdiagnosed clinical genetics entity?

Abstract: Summary: A new patient with Andermann syndrome: an underdiagnosed clinical genetics entity ': Andermann syndrome is an autosomal recessive disorder characterized by the agenesis of the corpus callosum and peripheral neuropathy (ACCPN) People affected by Andermann syndrome have mental retardation, areflexia and severe progressive neuropathy often accompanied by psychiatric symptoms, and they typically die in the third decade of their life We here report the case of a 5 year-old Turkish boy bom to consanguineous parents He presented to clinical attention with delayed development and epilepsy and was found to have dysmorphic characteristics, areflexia and severe neuropathy on exam Imaging studies were remarkable for agenesis of corpus callosum SLCI2A6 screening revealed the presence of R101IX mutation; potentially responsible for the changes in intracellular and extracellular ion concentrations, leading to defects in cortical electrical activityKey-words: Andermann Syndrome - EEG - SLCI2A6INTRODUCTIONPeripheral neuropathy associated with agenesis of the corpus callosum (ACCPN) or Andermann syndrome is an autosomal recessively inherited progressive disorder mostly seen in French-Canadians (FC) living in Saguenay-Lac-St-Jean and Charlevoix, Quebec In the first years of life the symptoms include slow developmental progress, mental retardation, areflexia and dysmorphic characteristics Between 4 and 6 years of age they are able to walk with support, later on, severe progression of motor and intellectual disabilities are observed along with psychiatric symptoms such as hallucinations, suggesting a progressive deterioration in the central nervous system Affected individuals typically die in the third decade of their life (5, 11) In 2002, Howard et al showed mutations in solute carrier family 12 member 6 (SLC12A6) gene, encoding the potassium-chloride (K+-C1) cotransporter 3 (KCC3) protein, to be causative in the ACCPN syndrome (11) Other than the French-Canadian population, Andermann syndrome is reported to be most prevalent among Turkish patients Here we report the presence of a R101IX mutation in a 5 year-old Turkish boy who presented to medical attention at 1 year-of-age with delayed development and epilepsyCASE REPORTA one year-old boy was admitted to the child neurology clinic because of developmental delay He was prematurely bom at week 31 at 2200 g through vaginal delivery He was not reported to have newborn jaundice nor perinatal asphyxia, and did not need an incubator or ventilator He did not speak any words and was reported to smile at 8 months, developed head control at 5 months and was able to sit up without support at 12 months He was the second living child of third-degree consanguineous parents The mother was 26 years old at the time with a healthy 8 year-old daughter and she also had a history of a terminated intrauterine pregnancy (via D&C) at 6-months reportedly due to a fetal brain abnormality Of note, the 30 year old father has a childless sister with mild mental retardation and a 20 year-old brother with moderate mental retardation who continues to receive special educationOn physical examination, the patient had dysmorphic characteristics which included hypertelorism, long face, slight ptosis, a high arched palate, separated teeth, proximally placed thumbs He had absent deep tendon reflexes (Fig 1) The rest of the physical exam was unremarkable Laboratory values including complete blood count, biochemistry tests including creatine kinase, thyroid function tests, urine and plasma aminoacid levels were all normal Agenesis of corpus callosum was detected by magnetic resonance imaging (MRI)The patient, who continues to receiving special education, began to say a few words at 2 years At 4 years of age, a electrophysiological study was performed which revealed demyelinization and axonal damage consistent with severe sensorimotor polyneuropathy …