Article

Identification of CC2D2A as a Meckel Syndrome Gene Adds an Important Piece to the Ciliopathy Puzzle

National Public Health Institute, Institute for Molecular Medicine Finland, Helsinki 00290, Finland.
The American Journal of Human Genetics (Impact Factor: 10.99). 07/2008; 82(6):1361-7. DOI: 10.1016/j.ajhg.2008.05.004
Source: PubMed

ABSTRACT Meckel syndrome (MKS) is a lethal malformation disorder characterized classically by encephalocele, polycystic kidneys, and polydactyly. MKS is also one of the major contributors to syndromic neural tube defects (NTDs). Recent findings have shown primary cilia dysfunction in the molecular background of MKS, indicating that cilia are critical for early human development. However, even though four genes behind MKS have been identified to date, they elucidate only a minor proportion of the MKS cases. In this study, instead of traditional linkage analysis, we selected 10 nonrelated affected fetuses and looked for the homozygous regions shared by them. Based on this strategy, we identified the sixth locus and the fifth gene, CC2D2A (MKS6), behind MKS. The biological function of CC2D2A is uncharacterized, but the corresponding polypeptide is predicted to be involved in ciliary functions and it has a calcium binding domain (C2). Immunofluorescence staining of patient's fibroblast cells demonstrates that the cells lack cilia, providing evidence for the critical role of CC2D2A in cilia formation. Our finding is very significant not only to understand the molecular background of MKS, but also to obtain additional information about the function of the cilia, which can help to understand their significance in normal development and also in other ciliopathies, which are an increasing group of disorders with overlapping phenotypes.

0 Followers
 · 
123 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Joubert (JBTS) and Meckel-Gruber (MKS) syndromes are recessive neurodevelopmental conditions caused by mutations in proteins that are structural or functional components of the primary cilium. In this review we provide an overview of their clinical diagnosis, management and molecular genetics. Both have variable phenotypes, extreme genetic heterogeneity, and display allelism both with each other and other ciliopathies. Recent advances in genetic technology have significantly improved diagnosis and clinical management of ciliopathy patients, with the delineation of some general genotype-phenotype correlations. We highlight those that are most relevant for clinical practice, including the correlation between TMEM67 mutations and the JBTS variant phenotype of COACH syndrome. The subcellular localization of the known MKS and JBTS proteins is now well-described, and we discuss some of the contemporary ideas about ciliopathy disease pathogenesis. Most JBTS and MKS proteins localize to a discrete ciliary compartment called the transition zone (TZ), and act as structural components of the so-called "ciliary gate" to regulate the ciliary trafficking of cargo proteins or lipids. Cargo proteins include enzymes and transmembrane proteins that mediate intracellular signaling. The disruption of TZ function may contribute to the ciliopathy phenotype by altering the composition of the ciliary membrane or axoneme, with impacts on essential developmental signaling including the Wnt and Shh pathways as well as the regulation of secondary messengers such as inositol-1,4,5-trisphosphate (InsP3) and cAMP. However, challenges remain in the interpretation of the pathogenic potential of genetic variants of unknown significance, and in the elucidation of the molecular mechanisms of phenotypic variability in JBTS and MKS. The further genetic and functional characterization of these conditions is essential to prioritize patients for new targeted therapies.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The majority of hearing loss and balance disorders are caused by the permanent loss of mechanosensory hair cells of the inner ear. Identification of genes and compounds that modulate susceptibility to hair cell death is frequently confounded by the difficulties of assaying for such complex phenomena in mammalian models. The zebrafish has emerged as a powerful animal model for genetic and chemical screening in many contexts. Several characteristics of the zebrafish, such as its small size and external location of mechanosensory hair cells within the lateral line sensory organ, uniquely position it as an ideal model organism for the study of hair cell toxicity. We have used this model to screen for genes and compounds that affect hair cell survival during ototoxin exposure and have identified agents that would not be expected to play a role in this process based on a priori knowledge of their function. The identification of such agents yields better understanding of hair cell death and holds promise to stem hearing loss and balance disorders in the human population.
    Frontiers in Cellular Neuroscience 02/2015; 9:46. DOI:10.3389/fncel.2015.00046 · 4.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To ascertain the incidence, and describe the various forms of neural tube defects (NTDs) due to genetic, chromosomal, and syndromic causes. We carried out a retrospective analysis of data retrieved from the medical records of newborn infants admitted to the Neonatal Intensive Care Unit with NTDs and their mothers spanning 14 years (1996-2009) at the Security Forces Hospital, Riyadh, Saudi Arabia. The cases were ascertained by a perinatologist, neonatologist, geneticist, radiologist, and neurologist. The literature was reviewed via a MEDLINE search. Only liveborn babies were included. Permission from the Educational Committee at the Security Forces Hospital was obtained prior to the collection of data. Out of 103 infants with NTDs admitted during this period, 20 (19.4%) were found to have an underlying genetic syndromic, chromosomal and/or other anomalies. There were 5 cases of Meckel-Gruber syndrome, 2 Joubert syndrome, one Waardenburg syndrome, one Walker-Warburg syndrome, 2 chromosomal disorders, 2 caudal regression, one amniotic band disruption sequence, one associated with omphalocele, one with diaphragmatic hernia, and 4 with multiple congenital anomalies. There is a high rate of underlying genetic syndromic and/or chromosomal causes of NTDs in the Saudi Arabian population due to the high consanguinity rate. Identification of such association can lead to more accurate provisions of genetic counseling to the family including preimplantation genetic diagnosis or early termination of pregnancies associated with lethal conditions.
    Saudi medical journal 12/2014; 35(12):S49-56. · 0.55 Impact Factor

Preview

Download
2 Downloads
Available from