Finding underlying genetic mechanisms of two patients with autism spectrum disorder carrying familial apparently balanced chromosomal translocations.

BACKGROUND: Genetic etiologies of autism spectrum disorders (ASD) are complex, and the genetic factors identified so far are very diverse. In complex genetic diseases such as ASD, de novo or inherited chromosomal abnormalities are valuable findings for researchers with respect to identifying the underlying genetic risk factors. With gene mapping studies on these chromosomal abnormalities, dozens of genes have been associated with ASD and other neurodevelopmental genetic diseases. In the present study, we aimed to idenitfy the causative genetic factors in patients with ASD who have an apparently balanced chromosomal translocation in their karyotypes. METHODS: For mapping the broken genes as a result of chromosomal translocations, we performed whole genome DNA sequencing. Chromosomal breakpoints and large DNA copy number variations (CNV) were determined after genome alignment. Identified CNVs and single nucleotide variations (SNV) were evaluated with VCF-BED intersect and Gemini tools, respectively. A targeted resequencing approach was performed on the JMJD1C gene in all of the ASD cohorts (220 patients). For molecular modeling, we used a homology modeling approach via the SWISS-MODEL. RESULTS: We found that there was no contribution of the broken genes or regulator DNA sequences to ASD, whereas the SNVs on the JMJD1C, CNKSR2 and DDX11 genes were the most convincing genetic risk factors for underlying ASD phenotypes. CONCLUSIONS: Genetic etiologies of ASD should be analyzed comprehensively by taking into account of the all chromosomal structural abnormalities and de novo or inherited CNV/SNVs with all possible inheritance patterns.

A novel homozygous RIPK4 variant in a family with severe Bartsocas-Papas syndrome.

Bartsocas-Papas syndrome (BPS) is a rare autosomal recessive disorder characterized by popliteal pterygia, syndactyly, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and genital malformations. Most of the BPS cases reported to date are fatal either in the prenatal or neonatal period. Causative genetic defects of BPS were mapped on the RIPK4 gene encoding receptor-interacting serine/threonine kinase 4, which is critical for epidermal differentiation and development. RIPK4 variants are associated with a wide range of clinical features ranging from milder ectodermal dysplasia to severe BPS. Here, we evaluated a consanguineous Turkish family, who had two pregnancies with severe multiple malformations compatible with BPS phenotype. In order to identify the underlying genetic defect, direct sequencing of the coding region and exon-intron boundaries of RIPK4 was carried out. A homozygous transversion (c.481G>C) that leads to the substitution of a conserved aspartic acid to histidine (p.Asp161His) in the kinase domain of the protein was detected. Pathogenicity predictions, molecular modeling, and cell-based functional assays showed that Asp161 residue is required for the kinase activity of the protein, which indicates that the identified variant is responsible for the severe BPS phenotype in the family.

RIPK4 suppresses the TGF-ß1 signaling pathway in HaCaT cells.

Receptor-interacting serine/threonine kinase 4 (RIPK4) and transforming growth factor-ß 1 (TGF-ß1) play critical roles in the development and maintenance of the epidermis. A negative correlation between the expression patterns of RIPK4 and TGF-ß signaling during epidermal homeostasis-related events and suppression of RIPK4 expression by TGF-ß1 in keratinocyte cell lines suggest the presence of a negative regulatory loop between the two factors. So far, RIPK4 has been shown to regulate nuclear factor-κB (NF-κB), protein kinase C (PKC), wingless-type MMTV integration site family (Wnt), and (mitogen-activated protein kinase) MAPK signaling pathways. In this study, we examined the effect of RIPK4 on the canonical Smad-mediated TGF-ß1 signaling pathway by using the immortalized human keratinocyte HaCaT cell line. According to our results, RIPK4 inhibits intracellular Smad-mediated TGF-ß1 signaling events through suppression of TGF-ß1-induced Smad2/3 phosphorylation, which is reflected in the upcoming intracellular events including Smad2/3-Smad4 interaction, nuclear localization, and TGF-ß1-induced gene expression. Moreover, the kinase activity of RIPK4 is required for this process. The in vitro wound-scratch assay demonstrated that RIPK4 suppressed TGF-ß1-mediated wound healing through blocking TGF-ß1-induced cell migration. In conclusion, our results showed the antagonistic effect of RIPK4 on TGF-ß1 signaling in keratinocytes for the first time and have the potential to contribute to the understanding and treatment of skin diseases associated with aberrant TGF-ß1 signaling.

Mutations in RIPK4 cause the autosomal-recessive form of popliteal pterygium syndrome.

The autosomal-recessive form of popliteal pterygium syndrome, also known as Bartsocas-Papas syndrome, is a rare, but frequently lethal disorder characterized by marked popliteal pterygium associated with multiple congenital malformations. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this malformation syndrome to chromosomal region 21q22.3. Direct sequencing of RIPK4 (receptor-interacting serine/threonine kinase protein 4) showed a homozygous transversion (c.362T>A) that causes substitution of a conserved isoleucine with asparagine at amino acid position 121 (p.Ile121Asn) in the serine/threonine kinase domain of the protein. Additional pathogenic mutations-a homozygous transition (c.551C>T) that leads to a missense substitution (p.Thr184Ile) at a conserved position and a homozygous one base-pair insertion mutation (c.777_778insA) predicted to lead to a premature stop codon (p.Arg260ThrfsX14) within the kinase domain-were observed in two families. Molecular modeling of the kinase domain showed that both the Ile121 and Thr184 positions are critical for the protein's stability and kinase activity. Luciferase reporter assays also demonstrated that these mutations are critical for the catalytic activity of RIPK4. RIPK4 mediates activation of the nuclear factor-κB (NF-κB) signaling pathway and is required for keratinocyte differentiation and craniofacial and limb development. The phenotype of Ripk4(-/-) mice is consistent with the human phenotype presented herein. Additionally, the spectrum of malformations observed in the presented families is similar, but less severe than the conserved helix-loop-helix ubiquitous kinase (CHUK)-deficient human fetus phenotype; known as Cocoon syndrome; this similarity indicates that RIPK4 and CHUK might function via closely related pathways to promote keratinocyte differentiation and epithelial growth.

Mutations of the gene encoding otogelin are a cause of autosomal-recessive nonsyndromic moderate hearing impairment.

Already 40 genes have been identified for autosomal-recessive nonsyndromic hearing impairment (arNSHI); however, many more genes are still to be identified. In a Dutch family segregating arNSHI, homozygosity mapping revealed a 2.4 Mb homozygous region on chromosome 11 in p15.1-15.2, which partially overlapped with the previously described DFNB18 locus. However, no putative pathogenic variants were found in USH1C, the gene mutated in DFNB18 hearing impairment. The homozygous region contained 12 additional annotated genes including OTOG, the gene encoding otogelin, a component of the tectorial membrane. It is thought that otogelin contributes to the stability and strength of this membrane through interaction or stabilization of its constituent fibers. The murine orthologous gene was already known to cause hearing loss when defective. Analysis of OTOG in the Dutch family revealed a homozygous 1 bp deletion, c.5508delC, which leads to a shift in the reading frame and a premature stop codon, p.Ala1838ProfsX31. Further screening of 60 unrelated probands from Spanish arNSHI families detected compound heterozygous OTOG mutations in one family, c.6347C>T (p.Pro2116Leu) and c. 6559C>T (p.Arg2187X). The missense mutation p.Pro2116Leu affects a highly conserved residue in the fourth von Willebrand factor type D domain of otogelin. The subjects with OTOG mutations have a moderate hearing impairment, which can be associated with vestibular dysfunction. The flat to shallow "U" or slightly downsloping shaped audiograms closely resembled audiograms of individuals with recessive mutations in the gene encoding α-tectorin, another component of the tectorial membrane. This distinctive phenotype may represent a clue to orientate the molecular diagnosis.

Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay.

BACKGROUND: Congenital forms of hearing impairment can be caused by mutations in the estrogen related receptor beta (ESRRB) gene. Our initial linkage studies suggested the ESRRB locus is linked to high caries experience in humans. METHODS: We tested for association between the ESRRB locus and dental caries in 1,731 subjects, if ESRRB was expressed in whole saliva, if ESRRB was associated with the microhardness of the dental enamel, and if ESRRB was expressed during enamel development of mice. RESULTS: Two families with recessive ESRRB mutations and DFNB35 hearing impairment showed more extensive dental destruction by caries. Expression levels of ESRRB in whole saliva samples showed differences depending on sex and dental caries experience. CONCLUSIONS: The common etiology of dental caries and hearing impairment provides a venue to assist in the identification of individuals at risk to either condition and provides options for the development of new caries prevention strategies, if the associated ESRRB genetic variants are correlated with efficacy.

Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.

In a large consanguineous family of Turkish origin, genome-wide homozygosity mapping revealed a locus for recessive nonsyndromic hearing impairment on chromosome 14q24.3-q34.12. Fine mapping with microsatellite markers defined the critical linkage interval to a 18.7 cM region flanked by markers D14S53 and D14S1015. This region partially overlapped with the DFNB35 locus. Mutation analysis of ESRRB, a candidate gene in the overlapping region, revealed a homozygous 7 bp duplication in exon 8 in all affected individuals. This duplication results in a frame shift and premature stop codon. Sequence analysis of the ESRRB gene in the affected individuals of the original DFNB35 family and in three other DFNB35-linked consanguineous families from Pakistan revealed four missense mutations. ESRRB encodes the estrogen-related receptor beta protein, and one of the substitutions (p.A110V) is located in the DNA-binding domain of ESRRB, whereas the other three are substitutions (p.L320P, p.V342L, and p.L347P) located within the ligand-binding domain. Molecular modeling of this nuclear receptor showed that the missense mutations are likely to affect the structure and stability of these domains. RNA in situ hybridization in mice revealed that Esrrb is expressed during inner-ear development, whereas immunohistochemical analysis showed that ESRRB is present postnatally in the cochlea. Our data indicate that ESRRB is essential for inner-ear development and function. To our knowledge, this is the first report of pathogenic mutations of an estrogen-related receptor gene.

Involvement of DFNB59 mutations in autosomal recessive nonsyndromic hearing impairment.

In a consanguineous Turkish family, a locus for autosomal recessive nonsyndromic hearing impairment (ARNSHI) was mapped to chromosome 2q31.1-2q33.1. Microsatellite marker analysis in the complete family determined the critical linkage interval that overlapped with DFNB27, for which the causative gene has not yet been identified, and DFNB59, a recently described auditory neuropathy caused by missense mutations in the DFNB59 gene. The 352-amino acid (aa) DFNB59 gene product pejvakin is present in hair cells, supporting cells, spiral ganglion cells, and the first three relays of the afferent auditory pathway. A novel homozygous nonsense mutation (c.499C>T; p.R167X) was detected in the DFNB59 gene, segregating with the deafness in the family. The mRNA derived from the mutant allele was found not to be degraded in lymphocytes, indicating that a truncated pejvakin protein of 166 aa may be present in the affected individuals. Screening of 67 index patients from additional consanguineous Turkish families with autosomal recessive hearing impairment revealed a homozygous missense mutation (c.547C>T; p.R183W) that segregates with the hearing impairment in one family. Furthermore, in a panel of 83 Dutch patients, two additional novel mutations (c.509_512delCACT; p.S170CfsX35 and c.731T>G; p.L244R), which were not present in ethnically matched controls, were found heterozygously. Together, our data indicate that also nonsense mutations in DFNB59 cause nonsyndromic hearing loss, but that mutations in DFNB59 are not a major cause of nonsyndromic hearing impairment in the Turkish and Dutch population.

HLA-E*0101/0103X is Associated with Susceptibility to Pemphigus Vulgaris: A Case-control Study.

Pemphigus vulgaris (PV) is a life-threatening, autoimmune blistering disease of the skin and mucous membranes. The relationship between PV and human leukocyte antigen (HLA) has been studied in several reports. Previous reports have demonstrated that HLA-E polymorphisms may have a role in the susceptibility to various autoimmune diseases. Our aim was to evaluate the role of HLA-E gene polymorphisms in the pathogenesis of PV in a Turkish population. A total of 49 patients with PV and 50 healthy subjects were enrolled into the study. We sequenced and analyzed the HLA-E gene from genomic DNA obtained from peripheral blood samples of the study groups. HLA-E haplotyping was performed by Sanger sequencing of PCR products of the HLA-E gene and HLA-E alleles determined by using SeqScape® software according to the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System. The frequency of the HLA-E*0101/*0103X genotype in male patients with PV was found to be significantly higher than in men in the control group (P=0.023). In addition, the frequency of the HLA-E*0103X/*0103X genotype was significantly lower in patients with PV than the control group (P=0.040). We also detected that the frequency of the HLA-E*0101/*0103X genotype in patients with mucocutaneous type PV and the frequency of the HLA-E*0101/*0101 genotype in patients with mucosal type PV was significantly higher than those in other types of PV (P=0.001 and P=0.006). The results of this study indicate that carrying the HLA-E*0101/0103X genotype may increase the risk of PV in male patients.

Analysis of centrosome and DNA damage response in PLK4 associated Seckel syndrome.

Microcephalic primordial dwarfism (MPD) is a group of autosomal recessive inherited single-gene disorders with intrauterine and postnatal global growth failure. Seckel syndrome is the most common form of the MPD. Ten genes are known with Seckel syndrome. Using genome-wide SNP genotyping and homozygosity mapping we mapped a Seckel syndrome gene to chromosomal region 4q28.1-q28.3 in a Turkish family. Direct sequencing of PLK4 (polo-like kinase 4) revealed a homozygous splicing acceptor site transition (c.31-3 A>G) that results in a premature translation termination (p.[=,Asp11Profs*14]) causing deletion of all known functional domains of the protein. PLK4 is a master regulator of centriole biogenesis and its deficiency has recently been associated with Seckel syndrome. However, the role of PLK4 in genomic stability and the DNA damage response is unclear. Evaluation of the PLK4-Seckel fibroblasts obtained from patient revealed the expected impaired centriole biogenesis, disrupted mitotic morphology, G2/M delay, and extended cell doubling time. Analysis of the PLK4-Seckel cells indicated that PLK4 is also essential for genomic stability and DNA damage response. These findings provide mechanistic insight into the pathogenesis of the severe growth failure associated with PLK4-deficiency.

Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss.

In two large Turkish consanguineous families, a locus for autosomal recessive nonsyndromic hearing loss (ARNSHL) was mapped to chromosome 6p21.3 by genome-wide linkage analysis in an interval overlapping with the loci DFNB53 (COL11A2), DFNB66, and DFNB67. Fine mapping excluded DFNB53 and subsequently homozygous mutations were identified in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene, also named tetraspan membrane protein of hair cell stereocilia (TMHS) gene, which was recently shown to be mutated in the "hurry scurry" mouse and in two DFNB67-linked families from Pakistan. In one family, we found a homozygous one-base pair deletion, c.649delG (p.Glu216ArgfsX26) and in the other family we identified a homozygous transition c.494C>T (p.Thr165Met). Further screening of index patients from 96 Turkish ARNSHL families and 90 Dutch ARNSHL patients identified one additional Turkish family carrying the c.649delG mutation. Haplotype analysis revealed that the c.649delG mutation was located on a common haplotype in both families. Mutation screening of the LHFPL5 homologs LHFPL3 and LHFPL4 did not reveal any disease causing mutation. Our findings indicate that LHFPL5 is essential for normal function of the human cochlea.

Leukoencephalopathy with thalamus and brainstem involvement and high lactate caused by novel mutations in the EARS2 gene in two siblings.

Leukoencephalopathy with thalamus and brainstem involvement, and high lactate (LTBL) is a recently identified disease related to mutations in the EARS2 gene encoding glutamyl-tRNA synthetase. We report clinical and radiological findings for two siblings with new pathogenic mutations in the EARS2 gene. Both patients showed symptoms of mild-type disease, but there were clinical differences between the two siblings. While the older brother had hypotonia and delayed developmental milestones, the younger brother had seizures and spasticity in the lower extremities. Brain magnetic resonance imaging (MRI) findings were quite similar for the two siblings. MRI findings were specific to LTBL. MRI lesions of the older sibling had regressed over time. Clinical and radiological improvement, as in the previously reported patients with LTBL, may be an important clue for diagnosis.

GJB2 mutations in Turkish patients with ARNSHL: prevalence and two novel mutations.

Mutations in the connexin 26 gene (GJB2) cause a significant proportion of prelingual non-syndromic autosomal recessive deafness in all populations studied so far. To determine the percentage of hearing loss attributed to GJB2 in northeast Turkey, 93 unrelated patients with autosomal recessive non-syndromic hearing loss (ARNSHL) were screened. Seven different mutations were found in 29 of the patients with severe to profound hearing loss. The 35delG mutation was the most common mutation, accounting for 76% of all mutant GJB2 alleles. Four already described mutations, W24X, 310del14, delE120 and R184P and two novel mutations, Q80K and P173S, were identified. The allelic Delta(GJB6-D13S1830), which can cause hearing loss in combination with GJB2 mutations, was not present in our patients. Our results are comparable to those reported in other regions in Turkey and indicate that GJB2 mutations account for about 30% of Turkish patients with ARNSHL. Besides 35delG, W24X and delE120 occur more than once in the Turkish ARNSHL population with a frequency of about 5%.

Identification of an ancestral haplotype of the 35delG mutation in the GJB2 (connexin 26) gene responsible for autosomal recessive non-syndromic hearing loss in families from the Eastern Black Sea Region in Turkey.

Mutations in the GJB2 gene have been shown to be the major cause of autosomal recessively inherited, prelingual, non-syndromic hearing loss. 35delG was found to be the most frequent mutation among Caucasians. In this study, we performed haplotype analysis of two large families with autosomal recessive non-syndromic hearing loss (totally 33 affected, 37 unaffected) from Trabzon (a city from the Eastern Black Sea region) by using polymorphic markers close to the 35delG mutation region, and identified a common haplotype, "2-6-4". The frequency of the mutant chromosomes having the 2-6-4 haplotype was compared between the Eastern Black Sea region and the other regions of Turkey and the difference was found to be significant (chi squared = 5.13/df = 1/p = 0.023). Also, when the frequency of mutant and wild type chromosomes having the 2-6-4 haplotype was compared in the Eastern Black Sea region, a statistically significant difference was observed in the mutant chromosomes (chi squared = 7.46/df = 1/p < or = 0.01). The results of this study demonstrate that the ancestral haplotype of the chromosomes bearing 35delG mutation in the Eastern Black Sea region is "2-6-4".

Pyloric atresia-junctional epidermolysis bullosa syndrome showing novel c.4505-4508insACTC mutations in integrin b4 gene (ITGB4).

Epidermolysis bullosa (EB) is a group of inherited blistering skin diseases that vary widely in their pathogenesis and severity. It has been divided into distinct subtypes depending on the level of tissue separation in the dermal- epidermal basement membrane zone. There are four main categories of EB: simplex, junctional, dystrophic and Kindler syndrome. Junctional epidermolysis bullosa with pyloric atresia (JEB-PA) is a rare autosomal recessive form and characterized by severe mucocutaneous blisters and gastric outlet obstruction. Most of the mutations in JEP-PA are associated with the α6ß4 integrin genes (ITGA6, ITGB4,). Herein, we present a female newborn with lethal JEB-PA caused by a novel beta4 integrin mutation.

X-linked spinal and bulbar muscular atrophy without proximal atrophy.

We report on a case of genetically proven X-linked spinal and bulbar muscular atrophy (X-SBMA) with prominent distal muscle atrophy and without proximal muscle involvement. The patient was a 35-year-old man who had a history of slow progressive hand and distal leg muscle weakness and wasting for 10 years. Motor nerve conduction velocities were normal with reduced compound muscle action potential amplitudes of hand and foot muscles. Sensory action potential amplitudes were small. Needle EMG revealed a chronic partial denervation with reduced interference in hand and distal leg muscles but with normal heading in all tested proximal muscles. Genetic studied showed an expansion of CAG repeat in the first exon of the androgen receptor gene, which suggests diagnosis of X-SBMA. The importance of genetic studies in this patient with unusual clinical presentation is emphasized.

Novel splice-site and missense mutations in the ALDH1A3 gene underlying autosomal recessive anophthalmia/microphthalmia.

AIM: This study aimed to identify the underlying genetic defect responsible for anophthalmia/microphthalmia. METHODS: In total, two Turkish families with a total of nine affected individuals were included in the study. Affymetrix 250 K single nucleotide polymorphism genotyping and homozygosity mapping were used to identify the localisation of the genetic defect in question. Coding region of the ALDH1A3 gene was screened via direct sequencing. cDNA samples were generated from primary fibroblast cell cultures for expression analysis. Reverse transcriptase PCR (RT-PCR) analysis was performed using direct sequencing of the obtained fragments. RESULTS: The causative genetic defect was mapped to chromosome 15q26.3. A homozygous G>A substitution (c.666G>A) at the last nucleotide of exon 6 in the ALDH1A3 gene was identified in the first family. Further cDNA sequencing of ALDH1A3 showed that the c.666G>A mutation caused skipping of exon 6, which predicted in-frame loss of 43 amino acids (p.Trp180_Glu222del). A novel missense c.1398C>A mutation in exon 12 of ALDH1A3 that causes the substitution of a conserved asparagine by lysine at amino acid position 466 (p.Asn466Lys) was observed in the second family. No extraocular findings-except for nevus flammeus in one affected individual and a variant of Dandy-Walker malformation in another affected individual-were observed. Autistic-like behaviour and mental retardation were observed in three cases. CONCLUSIONS: In conclusion, novel ALDH1A3 mutations identified in the present study confirm the pivotal role of ALDH1A3 in human eye development. Autistic features, previously reported as an associated finding, were considered to be the result of social deprivation and inadequate parenting during early infancy in the presented families.

Investigation of CYP21A2 mutations in Turkish patients with 21-hydroxylase deficiency and a novel founder mutation.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessively inherited disorders characterized by impaired production of adrenal steroids. Approximately 95% of all CAH are caused by mutations of the CYP21A2 that encodes 21-hydroxylase. In this study, mutation analyses of CYP21A2 were performed in 48 CAH patients from 45 Turkish families with the clinical diagnosis of 21-hydroxylase deficiency (21OHD). While in 39 (86.7%) of 21OHD patients, disease causing CYP21A2 mutations were identified in both alleles, in two 21OHD patients CYP21A2 mutations were identified only in one allele. In four patients, mutation was not detected at all. In total, seventeen known and one novel, disease causing CYP21A2 mutations were observed. Among identified mutations, previously described c.293-13C/A>G, large rearrangements and p.Q319X mutations were the most common mutations accounting for 33.3%, 14.4% and 12.2% of all evaluated chromosomes, respectively. In six families (13.3%) a novel founder mutation, c.2T>C (p.M1?), inactivating the translation initiation codon was found. This mutation is not present in pseudogene CYP21A1P and causes the classical form of the disease in six patients. In addition, depending on the nature of the rearrangements CYP21A1P/CYP21A2 chimeras were further classified as CH(c/d), and CH-1(c) was shown to be the most prominent chimera in our study group. In conclusion, with this study we identified a novel founder CYP21A2 mutation and suggest a further classification for CYP21A1P/CYP21A2 chimeras depending on the combination of junction site position and whether it is occurred as a result of deletion or conversion. Absence of disease causing mutation of CYP21A2 in ten of screened ninety chromosomes suggests the contribution of regulatory elements in occurrences of CAH due to the 21OHD.

Penicillin induced epileptiform activity and EEG spectrum analysis of BDNF heterozygous mice: an in vivo electrophysiological study.

Brain-derived neurotrophic factor (BDNF) heterozygous mice (BDNF (+/-)) kindle slowly and have a higher seizure threshold. However, BDNF (+/-) mice exhibit reduced cortical inhibition and disrupted balance of excitation/inhibition synaptic transmission. We investigated penicillin-induced focal cortical epileptiform activity and electroencephalogram (EEG) spectral power of BDNF (+/-) mice, by using electrocorticogram (ECoG) recordings. BDNF (+/-) mice (n=10) and wild type littermates (n=9) were anesthetized with i.p. urethane (1.750g/kg). The recordings of ECoG were carried out by using a data acquisition system and 100IU penicillin was administered intracortically to induce epileptiform activity. The latencies for the onset of spikes and the amplitude of the spikes showed no differences. However the frequency of the spikes was significantly lower in BDNF (+/-) mice at 40th and 45th min following penicillin injection. Additionally, the EEG power for both BDNF (+/-) and wild type mice reduced after penicillin injection and enhanced during epileptiform activity. The spectral power analysis also revealed that the absolute Gamma power of BDNF (+/-) was significantly smaller than wild types. The results of the present study provide the first in vivo electrophysiological evidence that BDNF heterozygous mice exhibited suppressed epileptiform activity. Moreover, reduced levels of BDNF led to a reduction of absolute Gamma band power.

CEP152 is a genome maintenance protein disrupted in Seckel syndrome.

Functional impairment of DNA damage response pathways leads to increased genomic instability. Here we describe the centrosomal protein CEP152 as a new regulator of genomic integrity and cellular response to DNA damage. Using homozygosity mapping and exome sequencing, we identified CEP152 mutations in Seckel syndrome and showed that impaired CEP152 function leads to accumulation of genomic defects resulting from replicative stress through enhanced activation of ATM signaling and increased H2AX phosphorylation.