Mutations in CACNA1F are known to cause the incomplete form of X-linked congenital stationary night blindness (CSNB2). Since the clinical picture of AIED is quite similar to CSNB2, it has long been discussed whether these disorders are allelic or form a single entity. The present study clearly indicates that AIED is also caused by a novel CACNA1F gene mutation.
Clarin 1 (CLRN1) is a four-transmembrane protein expressed in cochlear hair cells and neural retina, and when mutated it causes Usher syndrome type 3 (USH3). The main human splice variant of CLRN1 is composed of three exons that code for a 232-aa protein. In this study, we aimed to refine the structure of CLRN1 by an examination of transcript splice variants and promoter regions. Analysis of human retinal cDNA revealed 11 CLRN1 splice variants, of which 5 have not been previously reported. We studied the regulation of gene expression by several promoter domains using a luciferase assay, and identified 1000 nt upstream of the translation start site of the primary CLRN1 splice variant as the principal promoter region. Our results suggest that the CLRN1 gene is significantly more complex than previously described. The complexity of the CLRN1 gene and the identification of multiple splice variants may partially explain why mutations in CLRN1 result in substantial variation in clinical phenotype.
We describe a 4-year-old boy with an accessory right thumb, short and broad toes, cryptorchidism, micrognathia, abnormally modeled ears, and delayed speech development. The chromosome analysis of patient's peripheral blood lymphocytes by conventional GTG banding demonstrated a small deletion in the long arm of chromosome 1. Confirmation and defined localization of the deleted segment to chromosomal bands 1q25.3-q31.3 was obtained by high resolution prometaphase analysis. Molecular studies, using a set of polymorphic chromosome 1q specific microsatellite markers, localized the deletion between the markers D1S2127 and D1S1727 on the paternally inherited chromosome 1. The maximum physical distance between these markers is approximately 21 Mb. The previously described two patients with 1q25-q31 deletions both had severe clinical manifestations, just as the other 10 patients with the proposed "intermediate 1q deletion syndrome," associated with 1q25-q32 deletions. Distinct from all these patients, the clinical picture of our patient is markedly milder, i.e., without growth retardation, microcephaly, or clear mental retardation.
Hypomagnesemia with secondary hypocalcemia (HSH) is a rare inherited disease, characterised by neurological symptoms, such as tetany, muscle spasms and seizures, due to hypocalcemia. It has been suggested that HSH is genetically heterogeneous, but only one causative gene, TRPM6, on chromosome 9 has so far been isolated. We have now studied the genetic background of HSH in four Polish patients belonging to three families, and a HSH patient carrying an apparently balanced X;9 translocation. The translocation patient has long been considered as an example of the X-linked form of HSH. We identified six TRPM6 gene mutations, of which five were novel, in the Polish patients. All the alterations were either nonsense/splicing or missense mutations. The clinical picture of the patients was similar to the HSH patients reported earlier. No genotype -phenotype correlation could be detected. Sequencing did not reveal any TRPM6 or TRPM7 gene mutations in the female HSH patient with an X;9 translocation. Isolation of the translocation breakpoint showed that the chromosome 9 specific breakpoint mapped within satellite III repeat sequence. The X-chromosomal breakpoint was localised to the first intron of the vascular endothelial growth factor gene, VEGFD. No other sequence alterations were observed within the VEGFD gene. Even though the VEGFD gene was interrupted by the X;9 translocation, it seems unlikely that VEGFD is causing the translocation patient's HSH-like phenotype. Furthermore, re-evaluation of patient's clinical symptoms suggests that she did not have a typical HSH.
ABSTRACT.Purpose: The Finnish distribution of clinical Usher syndrome (USH) types is 40% USH3, 34% USH1 and 12% USH2. All patients with USH3 carry the founder mutation in clarin 1 (CLRN1), whereas we recently reported three novel myosin VIIA (MYO7A) mutations in two unrelated patients with USH1. This study was carried out to further investigate the USH mutation spectrum in Finnish patients. Methods: We analysed samples from nine unrelated USH patients ⁄ families without known mutations and two USH3 families with atypically severe phenotype. The Asper Ophthalmics USH mutation chip was used to screen for known mutations and to evaluate the chip in molecular diagnostics of Finnish patients. Results: The chip revealed a heterozygous usherin (USH2A) mutation, p.N346H, in one patient. Sequencing of MYO7A and ⁄ or USH2A in three index patients revealed two novel heterozygous mutations, p.R873W in MYO7A and c.14343+2T>C in USH2A. We did not identify definite pathogenic second mutations in the patients, but identified several probably nonpathogenic variations that may modify the disease phenotype. Possible digenism could not be excluded in two families segregating genomic variations in both MYO7A and USH2A, and two families with CLRN1 and USH2A. Conclusion: We conclude that there is considerable genetic heterogeneity of USH1 and USH2 in Finland, making molecular diagnostics and genetic counselling of patients and families challenging.
Aim: To perform genealogical and clinical studies in Finnish families with X linked ocular albinism (OA1), including characterisation of the potential misrouting of optic fibres by evaluating visual evoked magnetic fields (VEFs), and to determine the mutation behind the disease. Methods: Three families with OA1 were clinically examined. VEFs were measured in two affected males and in one female carrier to characterise the cortical activation pattern after monocular visual stimulation. The neuronal sources of the VEFs were modelled with equivalent current dipoles (ECDs) in a spherical head model. All coding exons of the OA1 gene were screened for mutations by single strand conformation analysis and direct polymerase chain reaction sequencing. Results: Genealogical studies revealed that the three families were all related. The affected males had foveal hypoplasia with reduced visual acuity varying from 20/200 to 20/50, variable nystagmus, iris transillumination, and hypopigmentation of the retinal pigment epithelium. The ECD locations corresponding to the VEFs revealed abnormal crossing of the optic fibres in both affected males, but not in the carrier female. A novel point mutation, leading to a STOP codon, was identified in the fifth exon of the OA1 gene. Conclusions:The data indicate that the novel mutation 640C.T in the OA1 gene is the primary cause of the eye disease in the family studied. VEFs with ECD analysis was successfully used to demonstrate abnormal crossing of the optic fibres.
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