Mapping the locus of atrophia areata, a helicoid peripapillary chorioretinal degeneration with autosomal dominant inheritance, to chromosome 11p15

Atrophia areata (AA) is an early onset autosomal dominant helicoidperipapillary chorioretinal degeneration, which was first demonstratedto be hereditary in an Icelandic family. It is characterizedby bilateral wing-shaped atrophic areas of the retina, radiatingfrom the optic disk. Primary complaints of affected individualsare due to refractive errors and scotomata associated with myopiawhich increases with age. A genome linkage search with 112 microsatelliteDNA markers resulted in the highest probability of locationfor AA on chromosome 11. We genotyped 18 polymorphic markerson chromosome 11 and seven showed significant linkage to AA.The markers D11S1323 and D11S902 on 11p15 flank the region encompassingthe gene for AA.     

A novel mutation in the gene encoding noggin is not causative in human neural tube defects

Neural tube defects (NTD) are a common birth defect, with both genetic and environmental contributions to their etiology. In mouse, null mutations in Noggin result in fully-penetrant NTDs. We investigated Noggin for mutations that may predispose to human NTDs in 202 NTD cases. One variant allele was identified in a male patient with myelomeningocele. The patient's father and a sibling also carried the variant allele, but neither was affected with an open NTD. DNA sequencing confirmed a C1064A missense mutation predicted to result in the conversion of residue 84 from proline to histidine. The variant found in the NTD patient is a newly identified variant, the role of which is uncertain.     

A new HLA-A1 mutation: a novel, null variant allele

From an unusually informative family of 8 with near identical parental haplotypes (a and c), which differed by a single nucleotide substitution, we identified a new HLA-A1 null variant. While serologic antigen typing initially showed a "blank" allele in maternal haplotype "c" and 2 male offspring, more sophisticated DNA molecular HLA typing subsequently revealed the presence of a novel HLA-A0101 allele. Sequence-based typing showed a point mutation consisting of a nucleotide substitution of a cytosine for a guanine at nucleotide 215 yielding an amino acid change of arginine to proline at codon 48 in exon 2 (R48P). The impact on the HLA and immunogenetics laboratory is the need to not assume that all blanks are homozygous, as well as the need for the availability of high-resolution DNA molecular typing to clarify new alleles and to detect HLA-A null variants.     

A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration

The disks of vertebrate photoreceptors are produced by outgrowths of the plasma membrane. Hence genes that encode retinal proteins targeted to plasma membrane protrusions represent candidates for inherited retinal degenerations. One such candidate is the gene encoding human prominin (mouse)-like 1 (PROML1, previously known as AC133 antigen) which belongs to the prominin family of 5-transmembrane domain proteins. Murine prominin (prom) shows a strong preference for plasma membrane protrusions in a variety of epithelial cells whereas PROML1 is expressed in retinoblastoma cell lines and adult retina. In the present study, molecular genetic analyses of a pedigree segregating for autosomal recessive retinal degeneration indicated that the affected individuals were homozygous for a nucleotide 1878 deletion in PROML1. This alteration is predicted to result in a frameshift at codon 614 with premature termination of translation. Expression of a similar prom deletion mutant in CHO cells indicated that the truncated protein does not reach the cell surface. Immunocytochemistry revealed that prom is concentrated in the plasma membrane evaginations at the base of the outer segments of rod photoreceptors. These findings suggest that loss of prominin causes retinal degeneration, possibly because of impaired generation of the evaginations and/or impaired conversion of the evaginations to disks.     

A novel DRB1 allele (DRB1*0815) defined in an Australian Aborigine

The nucleotide sequence reported in this paper has been submitted to GenBank and assigned the accession number U63802. The name DRB1*0815 was officially assigned by the WHO Nomenclature Committee in July 1996. This follows the agreed policy that, subject to the conditions stated in the most recent nomenclature report (10), names will be assigned to new sequences as they are identified. Lists of such new names will be published in the following WHO nomenclature report. The sequence known previously as DRB1*08Taree will now be known as DRB1*0815.     

A novel heterozygous mutation in the Indian hedgehog gene (IHH) is associated with brachydactyly type A1 in a Chinese family

Brachydactyly type A1 (BDA1) is caused by mutations in the Indian hedgehog gene, IHH, on chromosome 2q35-36. In this study, a large five-generation Chinese family with BDA1 was identified and characterized. All affected family members demonstrated significant homogeneous phenotype and some unique clinical features different from those associated with the reported BDA1 mutations in IHH. Linkage analysis showed that the BDA1 gene in the family was linked to marker D2S126 close to IHH with a LOD score of 4.74 at a recombination fraction of 0. DNA sequence analysis revealed a heterozygous C to T transition at nucleotide 461 of IHH, resulting in a novel T154I substitution. The T154I mutation co-segregated with all affected individuals in the family, and was not present in normal family members or 200 normal controls. These results expand the spectrum of clinical phenotype associated with IHH mutations.M. Liu and X. Wang contribute equally to this work     

Localization of the gene for progressive bifocal chorioretinal atrophy (PBCRA) to chromosome 6q

Progressive bifocal chorioretinal atrophy (PBCRA) is a rare,autosomal dominant congenital chorioretinal dystrophy. We haveperformed genetic linkage analysis on a five-generation BritishPedigree. Twopoint linkage analysis showed significant linkagewith nine microsatellite marker loci mapping to chromosome 6q.Multipoint analysis gave a maximum lod score of 11. 8 (     

A novel frameshift founder mutation in the cytochrome P450 1B1 (CYP1B1) gene is associated with primary congenital glaucoma in Morocco

Primary congenital glaucoma (PCG) is a heterogeneous autosomal recessive disorder caused by unknown developmental defect(s) of the anterior chamber of the eye. A member of the cytochrome P450 gene family, CYP1B1, was found to be mutated in PCG patients in different populations, albeit to a variable extent. In this study, CYP1B1 mutations were searched for in 32 unrelated PCG patients from Morocco. Two mutations were detected in 11 (34%) patients. One, 4339delG, is novel and causes a frameshift at residue 179. The other, G61E, was previously found in patients from Turkey and Saudi Arabia. Seven patients were homozygous for 4339delG and two other patients for G61E, whereas the two remaining patients were compound heterozygotes. The close association of 4339delG with a rare allele of D2S177, a microsatellite marker located 270 kb upstream of CYP1B1, strongly suggested a founder effect for 4339delG. The occurrence of this mutation was tentatively dated at between 900 and 1700 years ago. Typing 4339delG and G61E mutations should help to prevent blindness resulting from a delayed diagnosis of PCG in Morocco.     

A novel HLA-DR12 allele (DRB1*1206) found in a Korean B-cell line

At least 6 HLA-DRB1*12 alleles have been identified to date with nucleotide polymorphism occurring at codons 37, 57-58, 60, 67, 85 and 87. In this report, we describe the identification of another new HLA-DRB1*12 allele: DRB1*1206. This novel allele was found in an Epstein-Barr virus (EBV)-transformed Korean B-cell line "K-KT" having the HLA-phenotype A3, 24; B44, 61; Cw3; Bw4, 6; DR12, 13 during full-length cDNA isolation for cell line characterization and for production of HLA-DR recombinant proteins. The allele was identified initially by cycle sequencing of subcloned HLA-DRB full-length cDNA.