Novel variants in the LRP4 underlying Cenani-Lenz Syndactyly syndrome

Khan, Hammal; Chong, Angie En Qi; Bilal, Muhammad; Nawaz, Shoaib; Abdullah, Abdullah; Abbasi, Sanaullah; Hussain, Amir; Hussain, Shabir; Ullah, Imran; Ali, H. Raza; Xue, Shifeng; Ahmad, Wasim

doi:10.1038/s10038-021-00995-x

Cited by 7 publications

(8 citation statements)

References 26 publications

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“…In accord, mutant mice or bovine expressing the ECD without the transmembrane domain or ICD are able to survive but display syndactyly henotypes 66,67 , suggesting the ICD may be necessary for signaling to prevent mulefoot or syndactyly. Most Lrp4 mutations in patients with Cenani-Lenz syndrome (CLS) are recessive and believed to alter its expression or function [68][69][70][71] . In mice, neonatal lethality can be caused by null mutation or mutations missing a critical region in the ECD such as mitt and mte 18 .…”

Section: Discussionmentioning

confidence: 99%

Intrafusal-fiber LRP4 for muscle spindle formation and maintenance in adult and aged animals

et al. 2023

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Proprioception is sensed by muscle spindles for precise locomotion and body posture. Unlike the neuromuscular junction (NMJ) for muscle contraction which has been well studied, mechanisms of spindle formation are not well understood. Here we show that sensory nerve terminals are disrupted by the mutation of Lrp4, a gene required for NMJ formation; inducible knockout of Lrp4 in adult mice impairs sensory synapses and movement coordination, suggesting that LRP4 is required for spindle formation and maintenance. LRP4 is critical to the expression of Egr3 during development; in adult mice, it interacts in trans with APP and APLP2 on sensory terminals. Finally, spindle sensory endings and function are impaired in aged mice, deficits that could be diminished by LRP4 expression. These observations uncovered LRP4 as an unexpected regulator of muscle spindle formation and maintenance in adult and aged animals and shed light on potential pathological mechanisms of abnormal muscle proprioception.

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Section: Discussionmentioning

confidence: 99%

Intrafusal-fiber LRP4 for muscle spindle formation and maintenance in adult and aged animals

et al. 2023

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“…AFF3 has been identified as a target of the WNT/B‐Catenin signaling pathway 18 . Mutations in WNT pathway components LRP4 and APC cause Cenani‐Lenz Syndrome, in which syndactyly is a major characteristic 10,19,20 . Given the importance of WNT/B‐Catenin signaling in the developing limb, alterations to downstream targets such as AFF3 may affect the output of WNT signaling and cause limb defects.…”

Section: Discussionmentioning

confidence: 99%

“…Genomic DNA from blood of all available individuals was extracted using GenElute™ Blood Genomic DNA Kit (Sigma Aldrich, CA, USA). Affected member (III‐1) was exome sequenced as previously described 10 . Variant prioritization criteria included CADD‐phred score of ≥20, minor allele frequency of ≤0.001 in gnomAD and other population databases, exonic and splice sites variants (±12 bp).…”

Section: Methodsmentioning

confidence: 99%

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A novel variant in AFF3 underlying isolated syndactyly

et al. 2022

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Isolated syndactyly is a common limb malformation with limited known genetic etiology. We used exome sequencing to discover a novel heterozygous missense variant c.2915G > C: p.Arg972Pro in AFF3 on chromosome 2q11.2 in a family with isolated syndactyly in hands and feet. AFF3 belongs to a family of nuclear transcription activating factors and is involved in limb dorsoventral patterning. The variant Arg972Pro is located near the C terminus, a region that is yet to be associated with human disorders. Functional studies did not show a difference in the stability or subcellular localization of the mutant and wild type proteins. Instead, overexpression in zebrafish embryos suggests that Arg972Pro is a loss‐of‐function allele. These results suggest that variants in the C terminus of AFF3 may cause a phenotype distinct from previously characterized AFF3 variants.

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“…Mutations within the human LRP4 gene cause kidney malformations and complex syndactyly, which is also referred to as Cenani-Lenz syndrome (Li et al, 2010;Khan et al, 2022). A recent study suggested a role of LRP4 in vascular biology.…”

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confidence: 99%

Balancing WNT signalling in early forebrain development: The role of LRP4 as a modulator of LRP6 function

Geng

Paul

Kowalczyk

et al. 2023

Front. Cell Dev. Biol.

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The specification of the forebrain relies on the precise regulation of WNT/ß-catenin signalling to support neuronal progenitor cell expansion, patterning, and morphogenesis. Imbalances in WNT signalling activity in the early neuroepithelium lead to congenital disorders, such as neural tube defects (NTDs). LDL receptor-related protein (LRP) family members, including the well-studied receptors LRP5 and LRP6, play critical roles in modulating WNT signalling capacity through tightly regulated interactions with their co-receptor Frizzled, WNT ligands, inhibitors and intracellular WNT pathway components. However, little is known about the function of LRP4 as a potential modulator of WNT signalling in the central nervous system. In this study, we investigated the role of LRP4 in the regulation of WNT signalling during early mouse forebrain development. Our results demonstrate that LRP4 can modulate LRP5- and LRP6-mediated WNT signalling in the developing forebrain prior to the onset of neurogenesis at embryonic stage 9.5 and is therefore essential for accurate neural tube morphogenesis. Specifically, LRP4 functions as a genetic modifier for impaired mitotic activity and forebrain hypoplasia, but not for NTDs in LRP6-deficient mutants. In vivo and in vitro data provide evidence that LRP4 is a key player in fine-tuning WNT signalling capacity and mitotic activity of mouse neuronal progenitors and of human retinal pigment epithelial (hTERT RPE-1) cells. Our data demonstrate the crucial roles of LRP4 and LRP6 in regulating WNT signalling and forebrain development and highlight the need to consider the interaction between different signalling pathways to understand the underlying mechanisms of disease. The findings have significant implications for our mechanistic understanding of how LRPs participate in controlling WNT signalling.

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Novel variants in the LRP4 underlying Cenani-Lenz Syndactyly syndrome

Cited by 7 publications

References 26 publications

Intrafusal-fiber LRP4 for muscle spindle formation and maintenance in adult and aged animals

Intrafusal-fiber LRP4 for muscle spindle formation and maintenance in adult and aged animals

A novel variant in AFF3 underlying isolated syndactyly

Balancing WNT signalling in early forebrain development: The role of LRP4 as a modulator of LRP6 function

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