Evidence of neuronal migration disorders in Knobloch syndrome: Clinical and molecular analysis of two novel families

Kliemann, Suzana; Waetge, Ricardo T.L.; Suzuki, Oscar; Passos‐Bueno, Maria Rita; Rosemberg, Sérgio

doi:10.1002/ajmg.a.20070

Cited by 60 publications

(63 citation statements)

References 15 publications

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“…Direct functional analysis of the single C. elegans collagen XV/XVIII locus cle-1 indicates that this gene is involved in cell migration, in particular in axon guidance, with expression associated with neural cells [18,19], similar to col 18a1 in mammals [52]. Assuming that this function was shared (and directly inherited) from the shared ancestor of the vertebrate and C. elegans sequences, this indicates that the family underwent functional diversification following the duplication events.…”

Section: Discussionmentioning

confidence: 96%

Characterization of drCol 15a1b: A Novel Component of the Stem Cell Niche in the Zebrafish Retina

2010

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There is a clear need to develop novel tools to help improve our understanding of stem cell biology, and potentially also the utility of stem cells in regenerative medicine. We report the cloning, functional, and bioinformatic characterization of a novel stem cell marker in the zebrafish retina, drCol 15a1b. The expression pattern of drCol 15a1b is restricted to stem cell niches located in the central nervous system, whereas other collagen XVs are associated with muscle and endothelial tissues. Knocking down drCol 15a1b expression causes smaller eyes, ear defects, and brain edema. Microscopic analysis reveals enhanced proliferation in the morphant eye, with many mitotic nuclei located in the central retina, together with a delayed differentiation of the mature retinal cell types. Besides, several markers known to be expressed in the ciliary marginal zone display broader expression areas in morpholino-injected embryos, suggesting an anomalous diffusion of signaling effectors from the sonic hedgehog and notch pathways. These results indicate that drCol 15a1b is a novel stem cell marker in the central nervous system that has a key role in homing stem cells into specialized niches in the adult organism. Moreover, mutations in the hCol 18a1 gene are responsible for the Knobloch syndrome, which affects brain and retinal structures, suggesting that drCol 15a1b may function similarly to mammalian Col 18a1. Thus, our results shed new light on the signaling pathways that underlie the maintenance of stem cells in the adult organism while helping us to understand the role of extracellular matrix proteins in modulating the signals that determine stem cell differentiation, cell cycle exit and apoptosis.

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Section: Discussionmentioning

confidence: 96%

Characterization of drCol 15a1b: A Novel Component of the Stem Cell Niche in the Zebrafish Retina

2010

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“…Our groups and others have described NTDs in chromosomal and inherited syndromes, including trisomy 13 (13)(14)(15)(16), trisomy 18 (16 -19), trisomy 21, and 22q11.2 and 13q deletion syndromes (20)(21)(22)(23). In rare cases, syndromes that variably present with NTDs have been associated with a mutation in a single gene (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). Using traditional linkage disequilibrium, patient studies of individual (non-folate-related) candidate genes, including jumonji (JMJ) (37), apolipoprotein E (ApoE), apolipoprotein B (ApoB) (38), bone morphogenetic protein-4 (BMP4) (39), CITED2 (40), transcription factor AP2 (TFAP2) (41), multiple sequence homeobox-2 (MSX2) (41), PAX3 (42) and noggin (NOG) (43), have only rarely succeeded in ascribing attributable risk for NTDs to specific genes.…”

Section: Introductionmentioning

confidence: 99%

Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene

Bassuk

Muthuswamy

Boland³

et al. 2012

Human Molecular Genetics

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Neural tube defects (NTDs) are common birth defects of complex etiology. Family and population-based studies have confirmed a genetic component to NTDs. However, despite more than three decades of research, the genes involved in human NTDs remain largely unknown. We tested the hypothesis that rare copy number variants (CNVs), especially de novo germline CNVs, are a significant risk factor for NTDs. We used array-based comparative genomic hybridization (aCGH) to identify rare CNVs in 128 Caucasian and 61 Hispanic patients with non-syndromic lumbar-sacral myelomeningocele. We also performed aCGH analysis on the parents of affected individuals with rare CNVs where parental DNA was available (42 sets). Among the eight de novo CNVs that we identified, three generated copy number changes of entire genes. One large heterozygous deletion removed 27 genes, including PAX3, a known spina bifida-associated gene. A second CNV altered genes (PGPD8, ZC3H6) for which little is known regarding function or expression. A third heterozygous deletion removed GPC5 and part of GPC6, genes encoding glypicans. Glypicans are proteoglycans that modulate the activity of morphogens such as Sonic Hedgehog (SHH) and bone morphogenetic proteins (BMPs), both of which have been implicated in NTDs. Additionally, glypicans function in the planar cell polarity (PCP) pathway, and several PCP genes have been associated with NTDs. Here, we show that GPC5 orthologs are expressed in the neural tube, and that inhibiting their expression in frog and fish embryos results in NTDs. These results implicate GPC5 as a gene required for normal neural tube development.

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“…The functions of the LAR and extracellular matrix (ECM) interaction are not clear. Mutations in human collagen XVIII result in Knobloch's syndrome and defects in neural cell migrations (Kliemann et al, 2003). Mice lacking nidogen-1 exhibit motor deficits that suggest a neurological defect (Dong et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

The Two Isoforms of theCaenorhabditis elegansLeukocyte-Common Antigen Related Receptor Tyrosine Phosphatase PTP-3 Function Independently in Axon Guidance and Synapse Formation

Ackley¹,

Harrington²,

Hudson³

et al. 2005

J. Neurosci.

107

146

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Leukocyte-common antigen related (LAR)-like phosphatase receptors are conserved cell adhesion molecules that function in multiple developmental processes. The Caenorhabditis elegans ptp-3 gene encodes two LAR family isoforms that differ in the extracellular domain. We show here that the long isoform, PTP-3A, localizes specifically at synapses and that the short isoform, PTP-3B, is extrasynaptic. Mutations in ptp-3 cause defects in axon guidance that can be rescued by PTP-3B but not by PTP-3A. Mutations that specifically affect ptp-3A do not affect axon guidance but instead cause alterations in synapse morphology. Genetic double-mutant analysis is consistent with ptp-3A acting with the extracellular matrix component nidogen, nid-1, and the intracellular adaptor ␣-liprin, syd-2. nid-1 and syd-2 are required for the recruitment and stability of PTP-3A at synapses, and mutations in ptp-3 or nid-1 result in aberrant localization of SYD-2. Overexpression of PTP-3A is able to bypass the requirement for nid-1 for the localization of SYD-2 and RIM. We propose that PTP-3A acts as a molecular link between the extracellular matrix and ␣-liprin during synaptogenesis.

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Evidence of neuronal migration disorders in Knobloch syndrome: Clinical and molecular analysis of two novel families

Cited by 60 publications

References 15 publications

Characterization of drCol 15a1b: A Novel Component of the Stem Cell Niche in the Zebrafish Retina

Characterization of drCol 15a1b: A Novel Component of the Stem Cell Niche in the Zebrafish Retina

Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene

The Two Isoforms of theCaenorhabditis elegansLeukocyte-Common Antigen Related Receptor Tyrosine Phosphatase PTP-3 Function Independently in Axon Guidance and Synapse Formation

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