Identification of the first dominant mutation of LAMA5 gene causing a complex multisystem syndrome due to dysfunction of the extracellular matrix

Sampaolo, Simone; Napolitano, Filomena; Tirozzi, Alfonsina; Reccia, Mafalda Giovanna; Lombardi, Luca; Farina, Olimpia; Barra, Adriano; Cirillo, Federica; Melone, Mariarosa Anna Beatrice; Gianfrancesco, Fernando; Iorio, Giuseppe Di; Esposito, Teresa

doi:10.1136/jmedgenet-2017-104555

Cited by 40 publications

(33 citation statements)

References 36 publications

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“…In the literature, LAMA5 has been observed to cause complex multisystem syndromes (skin anomalies, muscle weakness, joint and internal organ ligament laxity, etc.) due to dysfunction of the extracellular matrix (Sampaolo et al, ). Such phenotypes were present in members of three generations in the paper.…”

Section: Discussionmentioning

confidence: 99%

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

et al. 2019

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Whole-exome sequencing (WES) is widely used to detect genetic mutations that cause Mendelian diseases, and has been successfully applied in combination with preimplantation genetic diagnosis (PGD) to avoid the transmission of genetic defects.We investigated 40 nonconsanguineous families with unexplained, recurrent fetal malformations (two or more malformed fetuses) from May 2016 to December 2018.Using Trio-WES, we identified 32 disease-associated variants in 40 families (80% positive rate), which were subsequently verified. Known Mendelian diseases were identified in 12 families (30%), highly suspected Mendelian diseases in 12 families (30%), variants with uncertain significance in 8 families (20%), and no noticeable variants for 8 families (20%). Further analysis showed variants in 22 genes may cause fetal malformations. Four gene variants were detected in fetuses for the first time, which expanded the spectrum of the disease phenotype. Two novel candidate genes may be related to fetal malformations. Of 26 couples receiving PGD on diseaseassociated genes, 3 healthy newborns were delivered, and 4 couples are undergoing pregnancies. We reported the fetal data and developed an optimized genetic testing strategy. Our finding strongly suggests the presence of single gene Mendelian disorders in 60% of those families, and PGD services for couples to have healthy babies.

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Section: Discussionmentioning

confidence: 99%

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

et al. 2019

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“…The role of LN-α5 in promoting dermal papilla development and its function during early hair morphogenesis had been reported in mouse [14]. In addition, Simone and colleagues demonstrated the disease phenotype associated with LN-α5 mutation in humans including skin anomalies, impaired scarring, night blindness, muscle weakness, osteoarthritis, joint and internal organs ligaments laxity, malabsorption syndrome and hypothyroidism [15]. Thus, the qualitative and quantitative expressions of LN-α5 were different during the development stage as the regulatory molecules.…”

Section: Introductionmentioning

confidence: 99%

Down-Regulation of Laminin (LN)- α5 is Associated with Preeclampsia and Impairs Trophoblast Cell Viability and Invasiveness Through PI3K Signaling Pathway

Zhang

Xiong

Tong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Preeclampsia (PE) is a gestational disorder defined as hypertension and proteinuria, which is deemed a major cause of maternal and neonatal mortality and morbidity worldwide. The aim of this study was to investigate the expression patterns of placental laminin (LN)-α5 expression in normal and PE pregnancies, as well as evaluating the effects of LN-α5 on trophoblast proliferation, apoptosis, and invasion. Methods: LN-α5 expression levels were examined by reverse-transcriptase polymerase chain reaction (RT-PCR), and further confirmed by western blotting and immunofluorescence staining. Cell proliferation and apoptosis were measured by CCK-8 assay and flow cytometry. Cell invasion was assessed by matrigel-based transwell assay. LN-α5 DNA methylation in placentas was determined by bisulfite sequencing PCR (BSP). Results: LN-α5 expression levels in PE placentas were significantly lower than that of normal pregnancies. Deficiency in LN-α5 expression resulted in decreased trophoblast proliferation and invasion but increased cell apoptosis, meanwhile, PI3K/AKT/mTOR signaling pathway was impaired by LN-α5 silencing. LN-α5 promoter methylation didn’t show significant difference between PE and normal placentas. Conclusion: LN-α5 downregulation is associated with PE placenta and impairs trophoblast viability and invasiveness, which could be a causative factor of PE pathogenesis.

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“…22,23 We recently described a complex multisystem syndrome caused by an autosomal-dominant LAMA5 mutation in the second and third generations of an Italian family. 24 In this family, followed-up for 20 years, autosomal-dominant mild myopia was also observed as an independent trait. Clinical and genetic investigations on myopia, extended also to the fourth generation of the family, demonstrated that this trait was associated to a novel dominant missense variant c.1147A > G p.(Lys383Glu), in the prolyl 4-hydroxylase, alpha 2 (P4HA2) gene.…”

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confidence: 67%

“…Five subjects (II‐10, III‐7, III‐16, III‐18 and IV‐12) had uncorrected visual acuity 20/20 with emmetropia in both eyes, 6 patients (II‐4, II‐7, II‐9, III‐14, III‐17 and III‐20) had mild‐moderate myopia with a spherical equivalent of −3.05 ± 0.6D in the right eye and −2.4 ± 1.7D in the left eye. Patient III‐20 had myopia without the multisystem syndrome . Patient II‐4 was subjected to surgical refractive correction and his actual visual acuity is 8 to 9/10.…”

Section: Resultsmentioning

confidence: 99%

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Autosomal‐dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation

et al. 2018

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We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole-exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A > G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations.

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Identification of the first dominant mutation of LAMA5 gene causing a complex multisystem syndrome due to dysfunction of the extracellular matrix

Abstract: This is the first report of a disease phenotype associated with mutation in humans.

Cited by 40 publications

References 36 publications

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

Down-Regulation of Laminin (LN)- α5 is Associated with Preeclampsia and Impairs Trophoblast Cell Viability and Invasiveness Through PI3K Signaling Pathway

Autosomal‐dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation

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