Identification of mutations causing inherited retinal degenerations in the israeli and palestinian populations using homozygosity mapping.

PURPOSE: The Israeli and Palestinian populations are known to have a relatively high level of consanguineous marriages, leading to a relatively high frequency of autosomal recessive (AR) diseases. Our purpose was to use the homozygosity mapping approach, aiming to prioritize the set of genes and identify the molecular genetic causes underlying AR retinal degenerations in the Israeli and Palestinian populations. METHODS: Clinical analysis included family history, ocular examination, full-field electroretinography (ERG), and funduscopy. Molecular analysis included homozygosity mapping and mutation analysis of candidate genes. RESULTS: We recruited for the study families with AR nonsyndromic retinal degenerations, including mainly retinitis pigmentosa (RP), cone-rod degeneration (CRD), and Leber congenital amaurosis (LCA). With the aim to identify the causative genes in these families, we performed homozygosity mapping using whole genome single nucleotide polymorphism (SNP) arrays in 125 families. The analysis revealed the identification of 14 mutations, 5 of which are novel, in 16 of the families. The mutations were identified in the following eight genes: RDH12, PROM1, MFRP, TULP1, LCA5, CEP290, NR2E3, and EYS. While most patients had a retinal disease that is compatible with the causing gene, in some cases new clinical features are evident. CONCLUSIONS: Homozygosity mapping is a powerful tool to identify genetic defects underlying heterogeneous AR disorders, such as RP and LCA, in consanguineous and nonconsanguineous patients. The identification of significant and large homozygous regions, which do not include any known retinal disease genes, may be a useful tool to identify novel disease-causing genes, using next generation sequencing.

Mutations in CRB1 are a relatively common cause of autosomal recessive early-onset retinal degeneration in the Israeli and Palestinian populations.

PURPOSE: We evaluated the role of Crumbs homolog 1 (CRB1) in autosomal recessive (AR) retinal diseases in the Israeli and Palestinian populations using homozygosity mapping. METHODS: Clinical analysis included family history, ocular examination, full-field electroretinography (ERG), and funduscopy. Molecular analysis included homozygosity mapping using whole genome single nucleotide polymorphism (SNP) arrays and mutation analysis of CRB1. RESULTS: We recruited over 400 families with AR nonsyndromic retinal degenerations, including retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). SNP array analysis was performed on 175 index cases, eight of whom carried a homozygous region on chromosome 1 harboring CRB1. A subsequent CRB1 mutation analysis of the eight families, followed by screening of candidate founder mutations in the whole cohort of patients, revealed a total of 13 mutations, six of which are novel, in 15 families. Nine mutations were family-specific, and four were founder mutations identified in patients of Arab-Muslim origin, and Jews originated from Iraq and Kurdistan. Interestingly, a null mutation on at least one of the two mutated CRB1 alleles results in the LCA diagnosis, whereas patients carrying missense mutations were diagnosed with either RP or LCA. The average age at which CRB1 patients were referred to ERG testing was young (11 years). Of the 30 identified CRB1 patients, five had Coats-like exudative vasculopathy. CONCLUSIONS: Our data show that CRB1 mutations are a relatively frequent cause of AR early-onset retinal degeneration in the Israeli and Palestinian populations (10% of LCA families), and causes severe retinal degeneration at an early age.

Control of feeding in aplysia with ad libitum access to food: presence of food increases the intervals between feeding bouts.

The patterning of feeding and the quantity eaten in Aplysia californica with ad libitum food access cannot be explained by the effects of three variables previously shown to control the patterning of consummatory feeding responses and the quantity eaten in animals hand-fed individual meals. Feeding in ad libitum conditions is regulated primarily by varying the time between feeding bouts rather than by modulating bout lengths or the efficacy of consummatory movements within a bout. Aplysia with steady-state food access are in a newly characterized feeding state in which they are relatively unresponsive to food. They eat very little (1-4% of the time), and the quantity eaten is unrelated to the quantity of food in the anterior gut. The steady state can be maintained by the presence of food, even if animals do not contact food. The chemosensory rhinophores signal the presence of food that maintains the steady state. Up to 24 h without food is needed for animals to recover from the inhibition of feeding by steady-state presence of food. Recovery from the steady state is partially governed by postingestion stimuli as shown by a faster recovery in animals that have not been in contact with food. Inhibition of feeding during the steady-state is mediated in part via humoral factors because bathing the cerebral and buccal ganglia in hemolymph from animals in the steady state inhibits the ability to elicit buccal motor programs via a cholinomimetic thought to simulate stimulation of the lips with food. After food deprivation that is sufficiently long so that the steady-state decays, animals eat a large meal the size and dynamics of which are consistent with regulation via the three variables previously identified. This large meal is modulated by pheromones secreted by conspecifics even in sexually immature Aplysia.