Human microphthalmia associated with mutations in the retinal homeobox gene CHX10.

Isolated human microphthalmia/anophthalmia, a cause of congenital blindness, is a clinically and genetically heterogeneous developmental disorder characterized by a small eye and other ocular abnormalities. Three microphthalmia/anophthalmia loci have been identified, and two others have been inferred by the co-segregation of translocations with the phenotype. We previously found that mice with ocular retardation (the or-J allele), a microphthalmia phenotype, have a null mutation in the retinal homeobox gene Chx10 (refs 7,8). We report here the mapping of a human microphthalmia locus on chromosome 14q24.3, the cloning of CHX10 at this locus and the identification of recessive CHX10 mutations in two families with non-syndromic microphthalmia (MIM 251600), cataracts and severe abnormalities of the iris. In affected individuals, a highly conserved arginine residue in the DNA-recognition helix of the homeodomain is replaced by glutamine or proline (R200Q and R200P, respectively). Identification of the CHX10 consensus DNA-binding sequence (TAATTAGC) allowed us to demonstrate that both mutations severely disrupt CHX10 function. Human CHX10 is expressed in progenitor cells of the developing neuroretina and in the inner nuclear layer of the mature retina. The strong conservation in vertebrates of the CHX10 sequence, pattern of expression and loss-of-function phenotypes demonstrates the evolutionary importance of the genetic network through which this gene regulates eye development.

MEFV gene mutations and its impact on the clinical course in ulcerative colitis patients.

Ulcerative colitis (UC) is an inflammatory disease of the colonic mucosa. The presence of gene responsible for FMF, MEFV, which frequently causes inflammation, may aggravate the clinical course of UC. We aimed to determine the prevalence of MEFV mutations in UC patients and its impact on the clinical course. Four groups were formed as group 1 UC with distal disease, group 2 UC with pancolonic disease, group 3 UC with total colectomy, and group 4 Rheumatoid Arthritis (RA) patients. Eleven mutations of FMF gene were investigated. The mean age of group 1, 2, 3, and 4 were 46.7 ± 13.9, 43.8 ± 12.9, 44.8 ± 14.2, and 45.8 ± 10.9 years, respectively. The mutations were identified in 19 of the 54 UC patients (35.2%). Homozygous E148Q in 2 patients (3.7%) and heterozygous in 17 patients (31.5%) (E148Q 11.1%, M694V 5.6%, V726A 5.6%, K695R 1.8%, M680I 1.8%, and compound heterozygous 5.6%) were determined. Frequencies of MEFV mutations in group 1, 2, and 3 were 30, 27.3, and 58.3%, respectively. The mutations were identified in 3 of the 20 RA patients (15%). All of them were heterozygous. The rate of MEFV mutations were higher in group 3 than in group 4 (P = 0.018), and the number of attacks that were treated with steroid in all UC patients with mutation positive was higher than in mutation negative (P = 0.016). FMF gene mutations may be identified in UC patients up to 58.3%. It may be suggested that the UC patients with severe form should be identified for MEFV mutations before the judgment of colectomy.

Unusual combination of limb malformations in the same patient: brachydactyly with syndactyly and postaxial polydactyly of the hands and postaxial oligodactyly of the feet.

We report on a case with polydactyly, syndactyly and brachydactyly of the hands and oligodactyly of the feet, but no other anomalies and normal chromosome analysis. We compared the findings in our case with those of brachydactyly B, Fuhrmann syndrome and Haas-type syndactyly. However, it was not possible to suggest a syndrome diagnosis in the present case.

The importance of systematic genetic approach to familial schizophrenia cases and discussion of cryptic mosaic X chromosome aneuploidies in schizophrenia pathogenesis.

Abstract Objective. The aim of this study is to contribute to the understanding of schizophrenia genetics by using efficient algorithmic examination techniques including dysmorphic examination, karyotyping, and Fluoresence in situ hybridization (FISH). Methods. In this study we have investigated 20 familial schizophrenia patients from Turkey who had an affected first-degree relative. Dysmorphic examination of the schizophrenia cases and their relatives have been performed. High resolution banding (HRB), specific centromeric, subtelomeric and 22q11.2 region FISH probes were used for genotyping of patients. Results. Dysmorphic examination revealed ear, palate, nose, columella anomalies, and obesity in contributing patients, and the pale skin was noticed. The medical histories and clinical findings of two schizophrenia twins were almost identical. HRB study demonstrated the presence of 46,XX[55]/47,XXX[4]/48,XXXX[1] constitution in a paranoid schizophrenia case and 46,XX[67]/45,X[5] karyotype in her mother. FISH studies aiming subtelomeric chromosomal regions revealed no rearrangements and 22q11.2 regions were intact in all of the patients. Conclusions. The parental gonadal mosaicism lying at the origin of the mitotic aneuploidy may be the reason for mosaic X chromosome aneuploidies in our mother-daughter schizophrenia couple. Mosaic X chromosome aneuploidies may accompany schizophrenia cases and may contribute to pathogenesis of familial schizophrenia.