Maximum Logarithm Of The Odds Research Articles

Functional Mutation of SMAC/DIABLO, Encoding a Mitochondrial Proapoptotic Protein, Causes Human Progressive Hearing Loss DFNA64

SMAC/DIABLO is a mitochondrial proapoptotic protein that is released from mitochondria during apoptosis and counters the inhibitory activities of inhibitor of apoptosis proteins, IAPs. By linkage analysis and candidate screening, we identified a heterozygous SMAC/DIABLO mutation, c.377C>T (p.Ser126Leu, refers to p.Ser71Leu in the mature protein) in a six-generation Chinese kindred characterized by dominant progressive nonsyndromic hearing loss, designated as DFNA64. SMAC/DIABLO is highly expressed in human embryonic ears and is enriched in the developing mouse inner-ear hair cells, suggesting it has a role in the development and homeostasis of hair cells. We used a functional study to demonstrate that the SMAC/DIABLO(S71L) mutant, while retaining the proapoptotic function, triggers significant degradation of both wild-type and mutant SMAC/DIABLO and renders host mitochondria susceptible to calcium-induced loss of the membrane potential. Our work identifies DFNA64 as the human genetic disorder associated with SMAC/DIABLO malfunction and suggests that mutant SMAC/DIABLO(S71L) might cause mitochondrial dysfunction.

Homozygous feature of isolated triphalangeal thumb–preaxial polydactyly linked to 7q36: no phenotypic difference between homozygotes and heterozygotes

Preaxial polydactyly is a common limb malformation in humans with variable clinical expression. Different types of triphalangeal thumb-preaxial polydactyly phenotypes were mapped to the chromosome 7q36 region. We studied a large Turkish family of 69 individuals, of whom 22 individuals were affected. In all, 11 affected family members were clinically and radiologically evaluated. All affected individuals had a triphalangeal thumb and a preaxial (hypoplastic) extra digit bilaterally, with minimal intrafamilial variation. No feet involvement was observed. Linkage and haplotype analyses using 20 informative meioses confirmed the 7q36 region contained the LIMBR1 gene. Maximum logarithm of the odds (LOD) scores were obtained with DNA markers D7S550 and D7S2423. We have further identified a novel C to T alteration at position 4909 bp in the critical zone of polarizing activity regulatory sequence (ZRS) region, in the intron 5, of the LMBR1 gene. One affected male with homozygous status and no phenotypic difference from affected family members with heterozygous status represented the first homozygote case of the triphalangeal thumb-preaxial polydactyly phenotype.

Dyschromatosis universalis hereditaria: evidence for autosomal recessive inheritance and identification of a new locus on chromosome 12q21‐q23

Dyschromatosis universalis hereditaria (DUH) and dyschromatosis symmetrica hereditaria (DSH) are pigmentary dermatoses most commonly seen in Japan. Both disorders usually show autosomal dominant inheritance, although in some cases autosomal recessive inheritance was reported. DSH was mapped to chromosome 1q21.3, and mutations in the gene ADAR (DSRAD) were identified in Japanese, Chinese and Taiwanese families with autosomal dominant DSH. A second locus for dyschromatosis was mapped on chromosome 6q24.2-q25.2 in two Chinese families initially reported to be affected with DSH, but later suggested to have autosomal dominant DUH. The aim of this study was to investigate whether one of these two loci is involved in the development of DUH in a consanguineous Bedouin family from Saudi Arabia with four affected and three unaffected sibs, clearly pointing to autosomal recessive inheritance. After excluding mutations in ADAR and linkage to the candidate regions on chromosomes 1 and 6, we performed an single nucleotide polymorphism-based genome-wide scan for linkage with other loci. Under the assumption of autosomal recessive inheritance, we have identified a new locus for dyschromatosis on chromosome 12q21-q23 in this Arab family with a maximum logarithm of the odds (LOD) score of 3.4, spanning a distance of 18.9 cM. Our study revealed the first locus for autosomal recessive DUH and supports recent evidence that DSH and DUH are genetically distinct disorders.

A locus for autosomal dominant progressive non‐syndromic hearing loss, DFNA27, is on chromosome 4q12‐13.1

We ascertained a large North American family, LMG2, segregating progressive, non-syndromic, sensorineural hearing loss. A genome-wide scan identified significant evidence for linkage (maximum logarithm of the odds (LOD) score = 4.67 at theta = 0 for D4S398) to markers in a 5.7-cM interval on chromosome 4q12-13.1. The DFNA27 interval spans 8.85 Mb and includes at least 61 predicted and 8 known genes. We sequenced eight genes and excluded them as candidates for the DFNA27 gene.

Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus.

Inheritance of a defect in a neuronal mechanism that regulates response to auditory stimuli was studied in nine families with multiple cases of schizophrenia. The defect, a decrease in the normal inhibition of the P50 auditory-evoked response to the second of paired stimuli, is associated with attentional disturbances in schizophrenia. Decreased P50 inhibition occurs not only in most schizophrenics, but also in many of their nonschizophrenic relatives, in a distribution consistent with inherited vulnerability for the illness. Neurobiological investigations in both humans and animal models indicated that decreased function of the alpha 7-nicotinic cholinergic receptor could underlie the physiological defect. In the present study, a genome-wide linkage analysis, assuming autosomal dominant transmission, showed that the defect is linked [maximum logarithm of the odds (lod) score = 5.3 with zero recombination] to a dinucleotide polymorphism at chromosome 15q13-14, the site of the alpha 7-nicotinic receptor. Despite many schizophrenics' extremely heavy nicotine use, nicotinic receptors were not previously thought to be involved in schizophrenia. The linkage data thus provide unique new evidence that the alpha 7-nicotinic receptor gene may be responsible for the inheritance of a pathophysiological aspect of the illness.