Construction of a natural panel of 11p11.2 deletions and further delineation of the critical region involved in Potocki–Shaffer syndrome

Wakui, Keiko; Gregato, Guiliana; Ballif, Blake C.; Glotzbach, Caron D.; Bailey, K. A.; Kuo, Pao Lin; Sue, Whui Chen; Sheffield, Leslie J.; Irons, Mira; Gómez, Enrique Galán; Hecht, Jacqueline; Potocki, Lorraine; Shaffer, Lisa G.

doi:10.1038/sj.ejhg.5201366

Cited by 35 publications

(65 citation statements)

References 59 publications

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“…Mice with LRP4 floxed alleles (LRP4 f/f ) were described previously (Wu et al, 2012b). B6;C3-Tg(ACTA1-rtTA; tetO-Cre) mice were from The Jackson Laboratory (stock #012433), which carry two transgenes: tetO-Cre, which expresses Cre under the control of the tetracycline-responsive regulatory element tetO; and ACTA1-rtTA, which expresses reverse tetracycline-controlled transactivator rtTA under the control of the promoter of the human ␣ 1-actin gene ACTA1 or HSA (Rao and Monks, 2009).…”

Section: Methodsmentioning

confidence: 99%

“…Resulting tetO-Cre; ACTA1-rtTA; LRP4 f/f mice are referred as inducible muscle-specific LRP4 knock-out (imKO) mice. Genotyping of LRP4 f/f allele was performed as described previously (Wu et al, 2012b). tetO-Cre; ACTA1-rtTA was genotyped with primers: tetO-Cre with forward ACT GAG AGG TGG GAA GCT CA and reverse GGC GAG TTT ACG GGT TGT TA and for ACTA1-rtTA with primers: forward AGG TGT AGA GAA GGC ACT TA and reverse CTA ATC GCC ATC TTC CAG CA.…”

Section: Methodsmentioning

confidence: 99%

“…Agrin and MuSK do not directly interact (Glass et al, 1996); rather, MuSK activation by agrin requires LRP4, a member of the low-density lipoprotein (LDL) receptor (LDLR) family . Evidence indicates that LRP4 is a receptor of agrin (Weatherbee et al, 2006;Kim et al, 2008;Zong et al, 2012). It is necessary for NMJ formation and agrin-induced activation of MuSK and AChR clustering in muscle cells (Weatherbee et al, 2006;Kim et al, 2008;.…”

Section: Introductionmentioning

confidence: 99%

“…Evidence indicates that LRP4 is a receptor of agrin (Weatherbee et al, 2006;Kim et al, 2008;Zong et al, 2012). It is necessary for NMJ formation and agrin-induced activation of MuSK and AChR clustering in muscle cells (Weatherbee et al, 2006;Kim et al, 2008;. In addition, muscle LRP4 may also regulate presynaptic differentiation (Wu et al, 2012b;Yumoto et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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LRP4 Is Critical for Neuromuscular Junction Maintenance

et al. 2014

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The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, and is critical for control of muscle contraction. Its formation requires neuronal agrin that acts by binding to LRP4 to stimulate MuSK. Mutations have been identified in agrin, MuSK, and LRP4 in patients with congenital myasthenic syndrome, and patients with myasthenia gravis develop antibodies against agrin, LRP4, and MuSK. However, it remains unclear whether the agrin signaling pathway is critical for NMJ maintenance because null mutation of any of the three genes is perinatal lethal. In this study, we generated imKO mice, a mutant strain whose LRP4 gene can be deleted in muscles by doxycycline (Dox) treatment. Ablation of the LRP4 gene in adult muscle enabled studies of its role in NMJ maintenance. We demonstrate that Dox treatment of P30 mice reduced muscle strength and compound muscle action potentials. AChR clusters became fragmented with diminished junctional folds and synaptic vesicles. The amplitude and frequency of miniature endplate potentials were reduced, indicating impaired neuromuscular transmission and providing cellular mechanisms of adult LRP4 deficiency. We showed that LRP4 ablation led to the loss of synaptic agrin and the 90 kDa fragments, which occurred ahead of other prejunctional and postjunctional components, suggesting that LRP4 may regulate the stability of synaptic agrin. These observations demonstrate that LRP4 is essential for maintaining the structural and functional integrity of the NMJ and that loss of muscle LRP4 in adulthood alone is sufficient to cause myasthenic symptoms.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LRP4 Is Critical for Neuromuscular Junction Maintenance

et al. 2014

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“…For example, deletions of the 11p11p12 and 11p13 regions on the short arm of human chromosome (Chr) 11 have been identified in the Potocki-Shaffer syndrome (Shaffer et al 1993;Bartsch et al 1996;Potocki and Shaffer 1996) and the Wilm's tumor-aniridia-genitourinary abnormalities-mental retardation (WAGR) syndrome (Riccardi et al 1978;Francke et al 1979;Hittner et al 1979;Fryns et al 1981), respectively. Deletion analyses were important in identifying genes associated with clinical features of the syndromes: EXT2 for multiple exostoses and ALX4 for parietal foramina in Potocki-Shaffer syndrome (Ligon et al 1998;Wu et al 2000;Wakui et al 2005), WT1 for Wilm's tumor, and PAX6 for aniridia in WAGR syndrome (van Heyningen et al 1985;Glaser et al 1986Glaser et al , 1992Fantes et al 1992). Deletion analyses have also defined the extent of the deleted region in patients with combined PotockiShaffer and WAGR syndromes (McGaughran et al 1995;Brémond-Gignac et al 2005) as well as microdeletions 39 to PAX6, which prevent expression of PAX6 and cause aniridia (Lauderdale et al 2000;D'elia et al 2007;Davis et al 2008).…”

mentioning

confidence: 99%

Analysis of Pax6 Contiguous Gene Deletions in the Mouse, Mus musculus, Identifies Regions Distinct from Pax6 Responsible for Extreme Small-Eye and Belly-Spotting Phenotypes

et al. 2009

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In the mouse Pax6 function is critical in a dose-dependent manner for proper eye development. Pax6 contiguous gene deletions were shown to be homozygous lethal at an early embryonic stage. Heterozygotes express belly spotting and extreme microphthalmia. The eye phenotype is more severe than in heterozygous Pax6 intragenic null mutants, raising the possibility that deletions are functionally different from intragenic null mutations or that a region distinct from Pax6 included in the deletions affects eye phenotype. We recovered and identified the exact regions deleted in three new Pax6 deletions. All are homozygous lethal at an early embryonic stage. None express belly spotting. One expresses extreme microphthalmia and two express the milder eye phenotype similar to Pax6 intragenic null mutants. Analysis of Pax6 expression levels and the major isoforms excluded the hypothesis that the deletions expressing extreme microphthalmia are directly due to the action of Pax6 and functionally different from intragenic null mutations. A region distinct from Pax6 containing eight genes was identified for belly spotting. A second region containing one gene (Rcn1) was identified for the extreme microphthalmia phenotype. Rcn1 is a Ca 12 -binding protein, resident in the endoplasmic reticulum, participates in the secretory pathway and expressed in the eye. Our results suggest that deletion of Rcn1 directly or indirectly contributes to the eye phenotype in Pax6 contiguous gene deletions.

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