A novel mutation in the connexin 26 gene (GJB2) in a child with clinical and histological features of keratitis-ichthyosis-deafness (KID) syndrome.

BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal disorder, caused by heterozygous missense mutation in GJB2, encoding the gap junction protein connexin 26. The commonest mutation is the p.Asp50Asn mutation, and only a few other mutations have been described to date. AIM: To report the fatal clinical course and characterize the genetic background of a premature male neonate with the clinical and histological features of KID syndrome. METHODS: Genomic DNA was extracted from peripheral blood and used for PCR amplification of the GJB2 gene. Direct sequencing was used for mutation analysis. RESULTS: The clinical features included hearing impairment, ichthyosiform erythroderma with hyperkeratotic plaques, palmoplantar keratoderma, alopecia of the scalp and eyelashes, and a thick vernix caseosa-like covering of the scalp. On histological analysis, features characteristic of KID syndrome, such as acanthosis and papillomatosis of the epidermis with basket-weave hyperkeratosis, were seen. The skin symptoms were treated successfully with acitretin 0.5 mg/kg. The boy developed intraventricular and intracerebral haemorrhage, leading to hydrocephalus. His condition was further complicated by septicaemia and meningitis caused by infection with extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. Severe respiratory failure followed, and the child died at 46 weeks of gestational age (13 weeks postnatally). Sequencing of the GJB2 gene showed that the child was heterozygous for a novel nucleotide change, c.263C>T, in exon 2, leading to a substitution of alanine for valine at position 88 (p.Ala88Val). CONCLUSIONS: This study has identified a new heterozygous de novo mutation in the Cx26 gene (c.263C>T; p.Ala88Val) leading to KID syndrome.

Molecular mechanics study of the cyclic and unsymmetric diborane(4) compounds.

The results of a theoretical study on the structure of some diborane(4) compounds are presented in order to analyze the issue related to the relative stabilities of the 1,1- vs. 1,2-isomers. Through the employment of the molecular mechanics method, characteristic distances and angles are given and they are compared with available experimental data. In order to rationalize the results, the different energy components are discussed in a comparative fashion. We find a rather satisfactory agreement between theoretical and experimental data. Some possible future extensions are pointed out to complement this sort of analysis.

Identification and characterization of an inner ear-expressed human melanoma inhibitory activity (MIA)-like gene (MIAL) with a frequent polymorphism that abolishes translation.

To discover new cochlea-specific genes as candidate genes for nonsyndromic hearing impairment, we searched in The Institute of Genome Research database for expressed sequence tags isolated from the cochlea only. This led to the cloning and characterization of a human gene named melanoma inhibitory activity-like (MIAL; HGMW-approved symbol OTOR alias MIAL) gene. In situ hybridization revealed MIAL expression in a cell layer beneath the sensory epithelium of cochlea and vestibule of human fetal inner ear. No other human tissue, except fetal brain, showed expression of MIAL when analyzed by in situ hybridization or reverse transcription-polymerase chain reaction. The cDNA of the mouse homologue was also cloned and mapped about 80 cM from the top of mouse chromosome 2. In mouse, Mial was also expressed in the cochlea and the vestibule of the inner ear, as well as in brain, eye, limb, and ovary. Expression in mammalian cell cultures showed that MIAL is translated as an approximately 15-kDa polypeptide that is assembled into a covalently linked homodimer, modified by sulfation, and secreted from the cells via the Golgi apparatus. In the human MIAL gene, a frequent polymorphism was discovered in the translation initiation codon (ACG instead of ATG). Of 505 individuals, 48 (9.5%) were ATG/ACG heterozygous and 1 (0.2%) was homozygous for ACG. No MIAL protein was synthesized in cells transfected with cDNA of the ACG allele. The inner ear-restricted expression pattern and the existence of an inactive allele suggest that MIAL may contribute to inner-ear dysfunction in humans.

CNV, PINV and probe-evoked potentials in schizophrenics.

Distractibility and temporal modulation of attention in schizophrenics were studied using a visual reaction time task with additional auditory probe stimuli during the forewarning period or between trials. The probes were thought to exert a distracting influence, especially on schizophrenics, and at the same time they generated auditory EPs which allowed to track the modulation of cortical excitability during response preparation. The midline distribution of the terminal contingent negative variation (tCNV) and the amplitude of the postimperative negative variation (PINV) were clearly different in 20 DSM III-R schizophrenics, as compared with 20 alcoholics and 20 normal controls. In schizophrenics, the more frontal distribution of the tCNV was associated with a higher degree of psychopathology (measured with the Brief Psychiatric Rating Scale) and with delayed reactions. Probes between trials reduced tCNV and PINV in all subjects alike. However, this effect could not be attributed to distraction, because reaction times were faster in these trials, possibly due to an alerting effect of the auditory probes. The N100 and P300 amplitudes to probes in the forewarning period, i.e., during the negative potential shift of the CNV, were significantly enhanced in all groups. Apparently there is a state of increased cortical excitability during the CNV which is not selectively "tuned" toward relevant stimuli. In schizophrenia, the temporal and topographical regulation of this excitability is disturbed.

Information processing during eye tracking as revealed by event-related potentials in schizophrenics, alcoholics, and healthy controls.

To further explore the hypothesis that schizophrenics are more distractable and/or have reduced processing resources available, event-related potentials (ERPs) and smooth pursuit eye movements (SPEM) were investigated in 20 medicated schizophrenics, 19 detoxified chronic alcoholics, and in a control group of 20 healthy subjects. Groups were matched for age and education. Eye tracking tasks and auditory oddball tasks were performed separately as well as simultaneously. In addition, an eye tracking condition with a task-irrelevant tone sequence was used to assess the effect of distraction. Schizophrenics showed a trend for poorer SPEM performance; alcoholics had no dysfunction in this task. Tracking accuracy did not change in either group when additional auditory stimuli were presented. P300 latency was delayed in both schizophrenics and alcoholics. P300 amplitude showed no overall group difference but it increased during the dual task in normals whereas it remained constant in patients. N100 amplitude was generally larger during the more complex conditions indicating heightened unspecific arousal. It is suggested that normals use increased arousal to mobilize additional resources and to allocate them to stimulus evaluation but schizophrenics and alcoholics are unable to do so. Results are more conform to a limited resources concept than to a filter deficit model of cognitive disturbances in schizophrenia and alcoholism.