Polymerizing laminins are multi-domain basement membrane (BM) glycoproteins that self-assemble into cell-anchored planar lattices to establish the initial BM scaffold. Nidogens, collagen-IV and proteoglycans then bind to the scaffold at different domain loci to create a mature BM. The LN domains of adjacent laminins bind to each other to form a polymer node, while the LG domains attach to cytoskeletal-anchoring integrins and dystroglycan, as well as to sulfatides and heparan sulfates. The polymer node, the repeating unit of the polymer scaffold, is organized into a near-symmetrical triskelion. The structure, recently solved by cryo-electron microscopy in combination with AlphaFold2 modeling and biochemical studies, reveals how the LN surface residues interact with each other and how mutations cause failures of self-assembly in an emerging group of diseases, the LN-lamininopathies, that include LAMA2-related dystrophy and Pierson syndrome.

LAMB2 gene disorders present with different phenotypes. Pierson syndrome (PS) is a common phenotype associated with LAMB2 variants. Neuromuscular phenotype has been reported including hypotonia and developmental delay. However, neuromuscular junction abnormalities represented as congenital myasthenic syndrome (CMS) was reported in one adult patient only. Here, in this paper, we present two pediatric cases with a severe presentation of PS and have CMS so expanding the knowledge of LAMB2 related phenotypes. The first patient had hypotonia and global developmental delay. Targeted genetic testing panel demonstrated homozygous pathogenic variant in the LAMB2 gene (c.5182C>T, pGln1728*) which was reported by Maselli et al. 2009. Repetitive nerve stimulation (RNS) showed a decremental response at low frequency of 3 Hz. On the other hand, the second patient had profound weakness since birth. Tri-Whole exome sequencing showed homozygous pathogenic variant in the LAMB2 gene c.2890C>T, pArg964*. A trial of salbutamol did not improve the symptoms. Both patients passed away from sequala of PS. The spectrum of phenotypic changes associated with LAMB2 mutations is still expanding, and further investigation into the various clinical and morphologic presentations associated with these mutations is important to better identify and manage affected individuals.

UNASSIGNED: Laminin subunit beta-2 (LAMB2)-associated disease, termed Pierson syndrome, presents with congenital nephrotic syndrome, ocular symptoms, and neuromuscular symptoms. In recent years, however, the widespread use of next-generation sequencing (NGS) has helped to discover a variety of phenotypes associated with this disease. Therefore, we conducted this systematic review.
UNASSIGNED: A literature search of patients with LAMB2 variants was conducted, and 110 patients were investigated, including 12 of our patients. For genotype-phenotype correlation analyses, the extracted data were investigated for pathogenic variant types, the severity of nephropathy, and extrarenal symptoms. Survival analyses were also performed for the onset age of end-stage kidney disease (ESKD).
UNASSIGNED: Among all patients, 81 (78%) presented with congenital nephrotic syndrome, and 52 (55%) developed ESKD within 12 months. The median age at ESKD onset was 6.0 months. Kidney survival analysis showed that patients with biallelic truncating variants had a significantly earlier progression to ESKD than those with other variants (median age 1.2 months vs. 60.0 months, P < 0.05). Although the laminin N-terminal domain is functionally important in laminin proteins, and variants in the laminin N-terminal domain are said to result in a severe kidney phenotype such as earlier onset age and worse prognosis, there were no significant differences in onset age of nephropathy and progression to ESKD between patients with nontruncating variants located in the laminin N-terminal domain and those with variants located outside this domain.
UNASSIGNED: This study revealed a diversity of LAMB2-associated diseases, characteristics of LAMB2 nephropathy, and genotype-phenotype correlations.

OBJECTIVE: To describe the ocular and renal features, as well as outcomes of retinal detachment repair, in patients with a novel, homozygous laminin β-2 (LAMB2) pathogenic variant.
METHODS: Single-center retrospective chart review of patients with a homozygous variant, c.619T>C p.(Ser207Pro), in the LAMB2 gene.
METHODS: Eleven patients (22 eyes) from 4 families.
METHODS: Demographic data and ocular findings were recorded. Patients were recalled for a detailed renal evaluation.
METHODS: Ocular features, renal features, and outcomes of retinal detachment repair.
RESULTS: The mean age at presentation was 6.0 (range, 1-26) years. None of the study eyes had microcoria, and none of the patients had nephrotic-range proteinuria. The mean refraction and axial length were -7.9 diopters (range, -4.0 to -12.0 diopters) and 25.3 (range, 22.7-27.7) mm, respectively. Eleven eyes (50%) had cataract at presentation. Fifteen eyes had a clear view to the fundus and all showed tessellated myopic fundus, avascular peripheral retina evident clinically or on fluorescein angiography, and rudimentary fovea. Optic disc pallor was observed in 10 eyes (66.7%). Straightened retinal vessels, abnormal vascular emanation (situs inversus) from the optic disc, supernumerary vascular branching at the optic disc, and vascular tortuosity were observed in 10 (66.7%), 2 (13.4%), 2 (13.4%), and 2 (13.4%) eyes, respectively. Discrete areas of punched-out chorioretinal atrophy were observed in 4 (26.7%) eyes. Spectral-domain OCT showed retinal and choroidal thinning in 13 eyes (86.7%), retinoschisis temporal to the fovea in 2 eyes (13.4%), and rudimentary fovea in 15 eyes (100%). Among the 22 eyes, 14 eyes (63.6%) developed rhegmatogenous retinal detachment (RRD), mostly during childhood, of which 5 patients had bilateral RRD. Eight eyes were operated on and 6 (75%) achieved retinal reattachment at the last follow-up. The mean preoperative visual acuity was 20/300 and the mean postoperative visual acuity at the last follow-up was 20/400.
CONCLUSIONS: This study describes a distinct phenotype of LAMB2-related disease with a novel, homozygous LAMB2 variant, and further expands the spectrum of ophthalmic and renal features, and the molecular genetic basis, of LAMB2-related disease. Because the typical microcoria and nephrotic-range proteinuria might be absent, the retinal features can guide the diagnosis.
BACKGROUND: The authors have no proprietary or commercial interest in any materials discussed in this article.

Pierson syndrome and X-linked Alport syndrome result from pathogenic variants in LAMB2 and COL4A5, respectively, and both affect basement membranes in the kidney and the eye. This study describes the ocular features in an individual with a homozygous LAMB2 pathogenic variant and compares the reported abnormalities in Pierson syndrome with those in Alport syndrome.
A 28-year-old man who developed kidney failure 10 years previously and subsequently had an atrial septal defect repair was suspected of having genetic kidney disease on the basis of his likely diagnosis of Focal and Segmental Glomerulosclerosis (FSGS), his young age at presentation, and his cardiac anomaly. He then underwent Whole Exome Sequencing and a formal ophthalmological examination.
The patient was found to have a homozygous Likely Pathogenic missense variant (p.(Arg1719Cys)) in LAMB2 consistent with the diagnosis of Pierson syndrome. He had normal visual acuity, normal optic globe and cornea size, and normal lens appearance on direct examination. Upon further testing, his cornea demonstrated central thinning. There was also increased corneal endothelial pleomorphism, a reduced foveal reflex, and a blunted foveal curvature, similar to the features seen in X-linked Alport syndrome.
Our patient had a later onset form of Pierson syndrome or \"FSGS type 5, with or without ocular abnormalities,\" consistent with his \"milder\" LAMB2 missense variant. The resemblance of the ocular features in Pierson syndrome and X-linked Alport syndrome suggests that mutations in LAMB2 and COL4A5 have similar effects on basement membranes and the pathogenesis of ocular damage.

BACKGROUND: Pierson syndrome is a rare autosomal recessive disorder that causes congenital nephrotic syndrome, neurodevelopmental abnormalities, and several ocular signs. The Pierson syndrome is caused by a mutation of the LAMB2 gene, that encodes laminin beta 2, which is expressed in the glomerular basement membrane, in neuromuscular junctions, and within ocular structures. First described by Pierson et al., the ocular signs of Pierson syndrome include microcoria, which is most characteristic sign, as well as iris abnormalities, cataract, glaucoma, and retinal detachment.
METHODS: Herein, we report the case of a young female who, at 16 months, was diagnosed with congenital nephrotic syndrome, subsequently underwent a kidney transplant at age 4,did cataract surgery with IOL implantation in both eyes at age of 2 years and presented with ocular signs including high myopia, band keratopathy, t, nystagmus, retina, and optic nerve atrophy, she did not show nor did the family report any neurodevelopmental abnormalities. her genetic studies this missense variant c.970T< C p. (Cys324Arg) of LAMB2, later she developed spontaneous hyphema along with vitreous haemorrhage and increased intra ocular pressure in her left eye, she underwent cyclophotocouagulation to treat her high IOP.
CONCLUSIONS: LAMB 2 mutations can be associated with multiple ocular signs that varies from mild to severe form, we are her to report our case who did not present with the typical ocular sign of microcoria for PS, did not have any neurodevelopmental  abnormality and presented with hyphaemia 2ndry to iris neovascularisation with vitreous haemorrhage with neovascular glaucoma.

暂无摘要。

The laminins (LM) are a family of basement membranes glycoproteins with essential structural roles in supporting epithelia, endothelia, nerves and muscle adhesion, and signaling roles in regulating cell migration, proliferation, stem cell maintenance and differentiation. Laminins are obligate heterotrimers comprised of α, β and γ chains that assemble intracellularly. However, extracellularly these heterotrimers then assemble into higher-order networks via interaction between their laminin N-terminal (LN) domains. In vitro protein studies have identified assembly kinetics and the structural motifs involved in binding of adjacent LN domains. The physiological importance of these interactions has been identified through the study of pathogenic point mutations in LN domains that lead to syndromic disorders presenting with phenotypes dependent on which laminin gene is mutated. Genotype-phenotype comparison between knockout and LN domain missense mutations of the same laminin allows inferences to be drawn about the roles of laminin network assembly in terms of tissue function. In this review, we will discuss these comparisons in terms of laminin disorders, and the therapeutic options that understanding these processes have allowed. We will also discuss recent findings of non-laminin mediators of laminin network assembly and their implications in terms of basement membrane structure and function.

Pierson syndrome (PIERSS) is a rare autosomal recessive disorder characterized by the combination of congenital nephrotic syndrome (CNS) and extrarenal symptoms including ocular malformations and neurodevelopmental deficits. PIERSS is caused by biallelic pathogenic variants in the LAMB2 gene leading to the defects of β2-laminin, the protein mainly expressed in the glomerular basement membrane, ocular structures, and neuromuscular junctions. Severe complications of PIERSS lead to the fatal outcome in early childhood in majority of the cases. We report a case of 5-year-old girl with severe phenotype of PIERSS caused by biallelic functional null variants of the LAMB2 gene. Due to consequences of CNS, the patient required bilateral nephrectomy and peritoneal dialysis since early infancy. The course was additionally complicated by tubulopathy, life-threatening infections, severe hypertension, erythropoietin-resistant anemia, generalized muscular hypotonia, neurogenic bladder, profound neurodevelopmental delay, epilepsy, gastrointestinal problems, secondary hypothyroidism, and necessity of repeated ocular surgery due to microcoria, cataract, and nystagmus. Due to multidisciplinary efforts, at the age of 4 years, the kidney transplantation was possible. Currently, the renal graft has an excellent function; however, the girl presents severe neurodevelopmental delay. The report presents a unique long-term follow-up of severe PIERSS with a few new phenotypical findings. It highlights the clinical problems and challenges in management of this rare condition.

BACKGROUND: Both Pierson syndrome (PS) and isolated nephrotic syndrome can be caused by LAMB2 biallelic pathogenic variants. Only 15 causative splicing variants in the LAMB2 gene have been reported. However, the pathogenicity of most of these variants has not been verified, which may lead to incorrect interpretation of the functional consequence of these variants.
METHODS: Using high-throughput DNA sequencing and Sanger sequencing, we detected variants in a female with clinically suspected PS. A minigene splicing assay was performed to assess the effect of LAMB2 intron 20 c.2885-9C>A on RNA splicing. We also performed the immunohistochemical analysis of laminin beta-2 in kidney tissues.
RESULTS: Two novel LAMB2 heteroallelic variants were found: a paternally inherited variant c.2885-9C>A in intron 20 and a maternally inherited variant c. 3658C>T (p. (Gln1220Ter)). In vitro minigene assay showed that the variant c.2885-9C>A caused erroneous integration of a 7 bp sequence into intron 20. Immunohistochemical analysis revealed the absence of glomerular expression of laminin beta-2, the protein encoded by LAMB2.
CONCLUSIONS: We demonstrated the impact of a novel LAMB2 intronic variant on RNA splicing using the minigene assay firstly. Our results extend the mutational spectrum of LAMB2.