Cohen syndrome is an uncommon autosomal recessive disorder whose diagnosis is based on the clinical picture of nonprogressive psychomotor retardation and microcephaly, characteristic facial features, retinal dystrophy, and intermittent neutropenia. We have refined the critical region on chromosome 8q22 by haplotype analysis, and we report the characterization of a novel gene, COH1, that is mutated in patients with Cohen syndrome. The longest transcript (14,093 bp) is widely expressed and is transcribed from 62 exons that span a genomic region of approximately 864 kb. COH1 encodes a putative transmembrane protein of 4,022 amino acids, with a complex domain structure. Homology to the Saccharomyces cerevisiae VPS13 protein suggests a role for COH1 in vesicle-mediated sorting and transport of proteins within the cell.

The modulatory aminergic neurotransmitters are involved in practically all important physiological systems in the brain, and many of them are also involved in human central nervous system diseases, including Parkinson's disease, schizophrenia, Alzheimer's disease, and depression. The zebrafish brain aminergic systems share many structural properties with the mammalian systems. The noradrenergic, serotonergic, and histaminergic systems are highly similar. The dopaminergic systems also show similarities with the major difference being the lack of dopaminergic neurons in zebrafish mesencephalon. Development of automated quantitative behavioral analysis methods for zebrafish and imaging systems of complete brain neurotransmitter networks have enabled comprehensive studies on these systems in normal and pathological conditions. It is possible to visualize complete neurotransmitter systems in the whole zebrafish brain at an age when the fish already displays all major vital behaviors except reproduction. Alterations of brain dopaminergic systems with MPTP, the neurotoxin that in humans and rodents induces Parkinson's disease, induces both changes in zebrafish dopaminergic system and quantifiable abnormalities in motor behavior. Chemically-induced brain histamine deficiency causes an identifiable alteration in histaminergic neurons and terminal networks, and a clear change in swimming behavior and long-term memory. Combining the imaging techniques and behavioral methods with zebrafish genetics is likely to help reveal how the modulatory transmitter systems interact to produce important behaviors, and how they are regulated in pathophysiological conditions and diseases.

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Cohen syndrome is an autosomal recessive condition associated with developmental delay, facial dysmorphism, pigmentary retinopathy, and neutropenia. The pleiotropic phenotype, combined with insufficient clinical data, often leads to an erroneous diagnosis and has led to confusion in the literature. Here, we report the results of a comprehensive genotype-phenotype study on the largest cohort of patients with Cohen syndrome assembled to date. We found 22 different COH1 mutations, of which 19 are novel, in probands identified by our diagnostic criteria. In addition, we identified another three novel mutations in patients with incomplete clinical data. By contrast, no COH1 mutations were found in patients with a provisional diagnosis of Cohen syndrome who did not fulfill the diagnostic criteria ("Cohen-like" syndrome). This study provides a molecular confirmation of the clinical phenotype associated with Cohen syndrome and provides a basis for laboratory screening that will be valuable in its diagnosis.

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We describe eight members from two large Amish kindreds who share a phenotype characterized by early-onset pigmentary retinopathy and myopia, global developmental delay and mental retardation, microcephaly, short stature, hypotonia, joint hyperextensibility, small hands and feet, common facial appearance, and friendly disposition. Several of the children had intermittent granulocytopenia. The phenotypic occurrence in three siblings coupled with the increased coefficient of inbreeding in the Amish suggested that this disorder is autosomal recessive and due to a single founder allele. Despite similarity to the clinical features of Cohen syndrome, experienced dysmorphologists attending the 23rd David W. Smith Workshop suggested the facial gestalt of the Amish children was inconsistent with this diagnosis. We mapped the locus responsible for these individuals' phenotype to chromosome 8q22-q23, which contains the recently discovered Cohen syndrome gene, COH1. Complete sequencing of the COH1 gene identified a likely disease-causing frameshift mutation and a missense mutation in the Amish patients. A comparison of features among different Cohen syndrome populations with shared linkage to the COH1 locus or known COH1 gene mutations may allow for the determination of improved clinical criteria on which to suspect the diagnosis of Cohen syndrome. We conclude that facial gestalt seems to be an unreliable indicator of Cohen syndrome between ethnic populations, although it is quite consistent among affected individuals within a particular ethnic group. Other features common to almost all individuals with proven COH1 mutations, such as retinal dystrophy, myopia, microcephaly, mental retardation, global developmental delay, hypotonia, and joint hyperextensibility appear to be better clinical indicators of this disorder.

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