Novel GUCY2D mutation causes phenotypic variability of Leber congenital amaurosis in a large kindred.

BACKGROUND: Leber congenital amaurosis (LCA) is a severe retinal degenerative disease that manifests as blindness or poor vision in infancy. The purpose of this study was to clinically characterize and identify the cause of disease in a large inbred Bedouin Israeli tribe with LCA. METHODS: Thirty individuals of a single kindred, including eight affected with LCA, were recruited for this study. Patients' clinical data and electroretinography (ERG) findings were collected. Molecular analysis included homozygosity mapping with polymorphic markers and Sanger sequencing of candidate genes. RESULTS: Of the eight affected individuals of the kindred, nystagmus was documented in five subjects and keratoconus in three. Cataract was found in 5 of 16 eyes. Photopic and scotopic ERG performed in 5 patients were extinguished. All affected subjects were nearly blind, their visual acuity ranged between finger counting and uncertain light perception. Assuming autosomal recessive heredity of a founder mutation, studies using polymorphic markers excluded homozygosity of affected individuals at the genomic loci of all previously known genes associated with LCA, except GUCY2D. Sequencing of GUCY2D identified a novel missense mutation (c.2129C>T; p.Ala710Val) resulting in substitution of alanine by valine at position 710 within the protein kinase domain of the retina-specific enzyme guanylate cyclase 1 (GC1) encoded by GUCY2D. Molecular modeling implied that the mutation changes the conformation of the regulatory segment within the kinase styk-domain of GC1 and causes loss of its helical structure, likely inhibiting phosphorylation of threonine residue within this segment, which is needed to activate the catalytic domain of the protein. CONCLUSIONS: This is the first documentation of the p.Ala710Val mutation in GC1 and the second ever described mutation in its protein kinase domain. Our findings enlarge the scope of genetic variability of LCA, highlight the phenotypic heterogeneity found amongst individuals harboring an identical LCA mutation, and possibly provide hope for gene therapy in patients with this congenital blinding disease. As the Bedouin kindred studied originates from Saudi Arabia, the mutation found might be an ancient founder mutation in that large community.

Kohlschutter-Tonz syndrome: clinical and genetic insights gained from 16 cases deriving from a close-knit village in Northern Israel.

BACKGROUND: Kohlschutter-Tonz syndrome (KTS; MIM 22675) is a rare autosomal recessive disorder characterized by intellectual impairment, spasticity, epilepsy, and amelogenesis imperfecta. We have recently identified the causative gene and mutation underlying KTS, namely, p.R157X, corresponding to ROGDI c.571C>T, which creates a premature stop codon in ROGDI homolog (Drosophila), a gene of unknown function, in KTS patients of Druze origin. PATIENTS: To better delineate the phenotype of KTS, 16 cases (eight female, eight male), from seven families (five kindreds) originating from a Druze village in Northern Israel, all homozygous for the same deleterious mutation, were investigated. Medical records were reviewed, and a detailed medical history was obtained by interview of parents. RESULTS: Age at onset between six and 12 months of age and the intensity of convulsions were variably manifested by affected sibs and mirror the progression of mental and motor deterioration. Amelogenesis imperfecta and deficient speech occur in all cases. By late adolescence and early twenties, individuals with KTS are bedridden, fed by a gastrostomy tube, spastic, and practically have no cognitive and language perception. CONCLUSIONS: KTS, a genetic disease heralded by convulsions, "yellow teeth," and severe mental impairment, allows for a clinical variability as regarding age of onset and severity of seizures that per se predict the speed of mental deterioration. In all cases, however, the morbid course of the disease is ultimately equally devastating by the twenties.

The desmosterolosis phenotype: spasticity, microcephaly and micrognathia with agenesis of corpus callosum and loss of white matter.

Desmosterolosis is a rare autosomal recessive disorder of elevated levels of the cholesterol precursor desmosterol in plasma, tissue and cultured cells. With only two sporadic cases described to date with two very different phenotypes, the clinical entity arising from mutations in 24-dehydrocholesterol reductase (DHCR24) has yet to be defined. We now describe consanguineous Bedouin kindred with four surviving affected individuals, all presenting with severe failure to thrive, psychomotor retardation, microcephaly, micrognathia and spasticity with variable degree of hand contractures. Convulsions near birth, nystagmus and strabismus were found in most. Brain MRI demonstrated significant reduction in white matter and near agenesis of corpus callosum in all. Genome-wide linkage analysis and fine mapping defined a 6.75 cM disease-associated locus in chromosome 1 (maximum multipoint LOD score of six), and sequencing of candidate genes within this locus identified in the affected individuals a homozygous missense mutation in DHCR24 leading to dramatically augmented plasma desmosterol levels. We thus establish a clear consistent phenotype of desmosterolosis (MIM 602398).