LTBPs in biology and medicine: LTBP diseases

Rifkin, Daniel B.; Rifkin, William J.; Zilberberg, Lior

doi:10.1016/j.matbio.2017.11.014

Cited by 80 publications

(63 citation statements)

References 85 publications

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“…However, KIAA1024/MINAR1/UBTOR has not been reported as candidate gene for intellectual disability in large whole-exome sequencing studies [45][46][47][48][49]. Implication of Ltbp1 in heart development [50] and Emilin1 in skin homeostasis and blood pressure control [51] do not support any contribution of the variants in LTBP1 and EMILIN1 to the neurological anomalies in the two siblings. However, an effect of the MINAR1 variant p. (Ser855Tyr) on the patients' phenotype cannot yet be excluded based on limited data from literature.…”

Section: Plos Geneticsmentioning

confidence: 94%

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions

et al. 2020

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P/Q-type channels are the principal presynaptic calcium channels in brain functioning in neurotransmitter release. They are composed of the pore-forming Ca V 2.1 α 1 subunit and the auxiliary α2δ-2 and β 4 subunits. β 4 is encoded by CACNB4, and its multiple splice variants serve isoform-specific functions as channel subunits and transcriptional regulators in the nucleus. In two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy we identified rare homozygous variants in the genes LTBP1, EMILIN1, CACNB4, MINAR1, DHX38 and MYO15 by whole-exome sequencing. In silico tools, animal model, clinical, and genetic data suggest the p.(Leu126-Pro) CACNB4 variant to be likely pathogenic. To investigate the functional consequences of the CACNB4 variant, we introduced the corresponding mutation L125P into rat β 4b cDNA. Heterologously expressed wild-type β 4b associated with GFP-Ca V 1.2 and accumulated in presynaptic boutons of cultured hippocampal neurons. In contrast, the β 4b-L125P mutant failed to incorporate into calcium channel complexes and to cluster presynaptically. When co-expressed with Ca V 2.1 in tsA201 cells, β 4b and β 4b-L125P augmented the calcium current amplitudes, however, β 4b-L125P failed to stably complex with α 1 subunits. These results indicate that p.Leu125Pro disrupts the stable association of β 4b with native calcium channel complexes, whereas membrane incorporation, modulation of current density and activation properties of heterologously expressed channels remained intact. Wildtype β 4b was specifically targeted to the nuclei of quiescent excitatory cells. Importantly, the p.Leu125Pro mutation abolished nuclear targeting of β 4b in cultured myotubes and hippocampal neurons. While binding of β 4b to the known interaction partner PPP2R5D (B56δ) was not affected by the mutation, complex formation between β 4b-L125P and the neuronal TRAF2 and NCK

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Section: Plos Geneticsmentioning

confidence: 94%

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions

et al. 2020

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“…This subfamily (Figure 3) is built upon the three TGF-b proteins that cluster together in all trees, based on their recent origin and common regulation by LTBP (Rifkin et al 2018). Neither prototypical TGF-b nor LTBP are present in flies and neither Maverick nor Dawdle has any relationship with them.…”

Section: Tgf-b Subfamily Treesmentioning

confidence: 99%

TGF-β Prodomain Alignments Reveal Unexpected Cysteine Conservation Consistent with Phylogenetic Predictions of Cross-Subfamily Heterodimerization

Wisotzkey

Newfeld

2020

Genetics

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Evolutionary relationships between prodomains in the TGF-β family have gone unanalyzed due to a perceived lack of conservation. We developed a novel approach, identified these relationships, and suggest hypotheses for new regulatory mechanisms in TGF-β signaling. First, a quantitative analysis placed each family member from flies, mice, and nematodes into the Activin, BMP, or TGF-β subfamily. Second, we defined the prodomain and ligand via the consensus cleavage site. Third, we generated alignments and trees from the prodomain, ligand, and full-length sequences independently for each subfamily. Prodomain alignments revealed that six structural features of 17 are well conserved: three in the straitjacket and three in the arm. Alignments also revealed unexpected cysteine conservation in the “LTBP-Association region” upstream of the straitjacket and in β8 of the bowtie in 14 proteins from all three subfamilies. In prodomain trees, eight clusters across all three subfamilies were present that were not seen in the ligand or full-length trees, suggesting prodomain-mediated cross-subfamily heterodimerization. Consistency between cysteine conservation and prodomain clustering provides support for heterodimerization predictions. Overall, our analysis suggests that cross-subfamily interactions are more common than currently appreciated and our predictions generate numerous testable hypotheses about TGF-β function and evolution.

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“…Among them, LTBP2 encodes for the second isoform of the LTBP‐fibrillin superfamily (LTBP‐2) and its biallelic variants are associated with eye‐restricted phenotypes including (a) primary congenital glaucoma (PCG) and (b) microspherophakia/megalocornea and ectopia lentis with/without secondary glaucoma (MMEL‐SG; Ali et al, ; Désir et al, ). Apparently in contrast with such an observation, LTBP‐2 is expressed ubiquitously, especially in the eye, cardiovascular system, lungs, testes, skeletal muscles, liver, spleen, and placenta (Öklü & Hesketh, ; Rifkin, Rifkin, & Zilberberg, ). In fact, Ltbp2 knockout mice die during early embryogenesis (Shipley et al, ) and this suggests a key role of LTBP2 in human development.…”

Section: Introductionmentioning

confidence: 99%

“…The apparent restriction to eye of the disease in patients with biallelic LTBP2 variants has been explained by a presumed compensatory effect of the wild‐type orthologous LTBP4 (Rifkin et al, ). Accordingly, experiments demonstrate that LTBP‐2 and LTBP‐4 have similar functions in the eye and that the ocular defects observed in LTBP‐2 null mices are attenuated by LTBP‐4 ectopic expression (Fujikawa et al, ).…”

Section: Introductionmentioning

confidence: 99%

LTBP2‐related “Marfan‐like” phenotype in two Roma/Gypsy subjects with the LTBP2 homozygous p.R299X variant

Morlino

Alesi

Calì

et al. 2018

American J of Med Genetics Pt A

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Recessive variants in LTBP2 are associated with eye-restricted phenotypes including (a) primary congenital glaucoma and (b) microspherophakia/megalocornea and ectopia lentis with/without secondary glaucoma. Nosology of LTBP2 pathology in humans is apparently in contrast with the consolidated evidence of a wide expression of this gene in the developing embryo. Accordingly, in previously published patients with LTBP2-related eye disease, additional extraocular findings have been occasionally reported and include, among others, high-arched palate, tall stature, and variable cardiac involvement. Anyway, no emphasis was put on such systemic manifestations.Here, we report two unrelated Roma/Gypsy patients first ascertained for a multisystem disorder mainly characterized by primary congenital glaucoma, complex congenital heart defect, tall stature, long fingers, skin striae and dystrophic scarring, and resembling Marfan syndrome. Heart involvement was severe with polyvalvular heart dysplasia in one, and transposition of great arteries, thoracic arterial tortuosity, polyvalvular heart dysplasia, and neo-aortic root dilatation in the other. Both patients were homozygous for the recurrent c.895C>T[p.(R299X)] variant, typically found in individuals of Roma/Gypsy descent with an eye-restricted phenotype. Our findings point out LTBP2 as responsible of a systemic phenotype coherent with the community of syndromes related to anomalies in genes involved in the TGFβ-pathway. Among these disorders, LTBP2-related systemic disease emerges as a distinct condition with expanding prognostic implications and autosomal recessive inheritance.

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LTBPs in biology and medicine: LTBP diseases

Cited by 80 publications

References 85 publications

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions

TGF-β Prodomain Alignments Reveal Unexpected Cysteine Conservation Consistent with Phylogenetic Predictions of Cross-Subfamily Heterodimerization

LTBP2‐related “Marfan‐like” phenotype in two Roma/Gypsy subjects with the LTBP2 homozygous p.R299X variant

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