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JCI Insight Mar 2021Mutations in LAMB2, encoding laminin β2, cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense...
Mutations in LAMB2, encoding laminin β2, cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense mutations that have been identified affect primarily the N-terminus of laminin β2. On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the β2 LEa-LF-LEb domains are exclusively found in cases with isolated nephropathy. Here we report the clinical features of mild isolated nephropathy associated with 3 LAMB2 variants in the LEa-LF-LEb domains (p.R469Q, p.G699R, and p.R1078C) and their biochemical characterization. Although Pierson syndrome missense mutations often inhibit laminin β2 secretion, the 3 recombinant variants were secreted as efficiently as WT. However, the β2 variants lost pH dependency for heparin binding, resulting in aberrant binding under physiologic conditions. This suggests that the binding of laminin β2 to negatively charged molecules is involved in glomerular basement membrane (GBM) permselectivity. Moreover, the excessive binding of the β2 variants to other laminins appears to lead to their increased deposition in the GBM. Laminin β2 also serves as a potentially novel cell-adhesive ligand for integrin α4β1. Our findings define biochemical functions of laminin β2 variants influencing glomerular filtration that may underlie the pathogenesis of isolated nephropathy caused by LAMB2 abnormalities.
Topics: Animals; Extracellular Matrix; HEK293 Cells; Humans; Kidney Diseases; Laminin; Mice; Mice, Knockout; Mutation, Missense; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pupil Disorders
PubMed: 33749661
DOI: 10.1172/jci.insight.145908 -
Neuromuscular Disorders : NMD Jun 2024LAMB2 gene disorders present with different phenotypes. Pierson syndrome (PS) is a common phenotype associated with LAMB2 variants. Neuromuscular phenotype has been...
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.
Topics: Humans; Myasthenic Syndromes, Congenital; Male; Female; Eye Abnormalities; Laminin; Phenotype; Mutation; Abnormalities, Multiple; Infant; Neuromuscular Junction Diseases; Child, Preschool; Nephrotic Syndrome; Pupil Disorders
PubMed: 38723581
DOI: 10.1016/j.nmd.2024.03.007 -
The Journal of Clinical Endocrinology... Mar 2020Mutations in LAMB2, encoding the basement membrane protein, laminin β2, are associated with an autosomal recessive disorder characterized by congenital nephrotic...
CONTEXT
Mutations in LAMB2, encoding the basement membrane protein, laminin β2, are associated with an autosomal recessive disorder characterized by congenital nephrotic syndrome, ocular abnormalities, and neurodevelopmental delay (Pierson syndrome).
CASE DESCRIPTION
This report describes a 12-year-old boy with short stature, visual impairment, and developmental delay who presented with macroscopic hematuria and albuminuria. He had isolated growth hormone deficiency, optic nerve hypoplasia, and a small anterior pituitary with corpus callosum dysgenesis on his cranial magnetic resonance imaging, thereby supporting a diagnosis of optic nerve hypoplasia syndrome. Renal histopathology revealed focal segmental glomerulosclerosis. Using next-generation sequencing on a targeted gene panel for steroid-resistant nephrotic syndrome, compound heterozygous missense mutations were identified in LAMB2 (c.737G>A p.Arg246Gln, c.3982G>C p.Gly1328Arg). Immunohistochemical analysis revealed reduced glomerular laminin β2 expression compared to control kidney and a thin basement membrane on electron microscopy. Laminin β2 is expressed during pituitary development and Lamb2-/- mice exhibit stunted growth, abnormal neural retinae, and here we show, abnormal parenchyma of the anterior pituitary gland.
CONCLUSION
We propose that patients with genetically undefined optic nerve hypoplasia syndrome should be screened for albuminuria and, if present, screened for mutations in LAMB2.
Topics: Albuminuria; Child; Humans; Hypopituitarism; Laminin; Male; Mutation; Optic Nerve Hypoplasia; Phenotype
PubMed: 31769495
DOI: 10.1210/clinem/dgz216 -
Kidney International Jul 2020The importance of the glomerular basement membrane (GBM) in glomerular filtration is underscored by the manifestations of Alport and Pierson syndromes, caused by defects...
The importance of the glomerular basement membrane (GBM) in glomerular filtration is underscored by the manifestations of Alport and Pierson syndromes, caused by defects in type IV collagen α3α4α5 and the laminin β2 chain, respectively. Lamb2 null mice, which model the most severe form of Pierson syndrome, exhibit proteinuria prior to podocyte foot process effacement and are therefore useful for studying GBM permselectivity. We hypothesize that some LAMB2 missense mutations that cause mild forms of Pierson syndrome induce GBM destabilization with delayed effects on podocytes. While generating a CRISPR/Cas9-mediated analogue of a human LAMB2 missense mutation in mice, we identified a 44-amino acid deletion (LAMB2-Del44) within the laminin N-terminal domain, a domain mediating laminin polymerization. Laminin heterotrimers containing LAMB2-Del44 exhibited a 90% reduction in polymerization in vitro that was partially rescued by type IV collagen and nidogen. Del44 mice showed albuminuria at 1.8-6.0 g/g creatinine (ACR) at one to two months, plateauing at an average 200 g/g ACR at 3.7 months, when GBM thickening and hallmarks of nephrotic syndrome were first observed. Despite the massive albuminuria, some Del44 mice survived for up to 15 months. Blood urea nitrogen was modestly elevated at seven-nine months. Eight to nine-month-old Del44 mice exhibited glomerulosclerosis and interstitial fibrosis. Similar to Lamb2 mice, proteinuria preceded foot process effacement. Foot processes were widened but not effaced at one-two months despite the high ACRs. At three months some individual foot processes were still observed amid widespread effacement. Thus, our chronic model of nephrotic syndrome may prove useful to study filtration mechanisms, long-term proteinuria with preserved kidney function, and to test therapeutics.
Topics: Animals; Laminin; Mice; Mice, Knockout; Nephrotic Syndrome; Pupil Disorders
PubMed: 32456966
DOI: 10.1016/j.kint.2020.01.033 -
Ophthalmology. Retina Feb 2024To 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.
PURPOSE
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.
DESIGN
Single-center retrospective chart review of patients with a homozygous variant, c.619T>C p.(Ser207Pro), in the LAMB2 gene.
SUBJECTS
Eleven patients (22 eyes) from 4 families.
METHODS
Demographic data and ocular findings were recorded. Patients were recalled for a detailed renal evaluation.
MAIN OUTCOME MEASURES
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.
FINANCIAL DISCLOSURE(S)
The authors have no proprietary or commercial interest in any materials discussed in this article.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Infant; Young Adult; Eye Abnormalities; Myopia; Proteinuria; Retina; Retinal Detachment; Retrospective Studies
PubMed: 37678612
DOI: 10.1016/j.oret.2023.08.022 -
Molecular Genetics & Genomic Medicine Jul 2021Both Pierson syndrome (PS) and isolated nephrotic syndrome can be caused by LAMB2 biallelic pathogenic variants. Only 15 causative splicing variants in the LAMB2 gene...
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.
CONCLUSION
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.
Topics: Diagnosis, Differential; Female; Genetic Testing; HEK293 Cells; Humans; Infant; Laminin; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Point Mutation; Pupil Disorders; RNA Splicing
PubMed: 33982833
DOI: 10.1002/mgg3.1704 -
CEN Case Reports Aug 2021Biallelic pathogenic variants in the laminin β2 (LAMB2) gene, which encodes laminin β2, are associated with Pierson syndrome characterized by a congenital nephrotic...
Biallelic pathogenic variants in the laminin β2 (LAMB2) gene, which encodes laminin β2, are associated with Pierson syndrome characterized by a congenital nephrotic syndrome that rapidly progresses to end-stage renal disease, distinct ocular maldevelopment with bilateral microcoria, and neurodevelopmental deficits. However, the phenotypic spectrum of LAMB2-associated disorder is broader than expected, and cases with milder phenotypes such as isolated congenital or infantile nephrotic syndrome have also been reported. We report a patient with LAMB2-associated renal disorder showing an extremely mild phenotype. A 5-year-old girl presented with asymptomatic proteinuria and hematuria detected by urinalysis screening. She had been previously healthy without any additional renal symptoms. The serum albumin and creatinine levels were normal. Renal biopsy revealed minor glomerular abnormalities with occasional focal mesangial proliferation. Electron microscopy showed no structural changes in the glomerular basement membrane. Targeted sequencing of podocyte-related genes using next-generation sequencing was performed. As a result, previously reported biallelic pathogenic variants of the truncating variant (c.5073_5076dupCCAG) and a splice site variant (c.3797 + 5G > A) in the LAMB2 gene were detected, and the patient was diagnosed with LAMB2-associated renal disorder. Interestingly, a previously reported case with this splicing variant also showed an atypically mild phenotype. We suggest that clinicians should consider LAMB2-associated nephritis as an important differential diagnosis in children with asymptomatic proteinuria and microscopic hematuria if there is no structural change in the glomerular basement membrane. A comprehensive gene-screening system using next-generation sequencing is useful for diagnosing these atypical cases with isolated urine abnormalities.
Topics: Child; Female; High-Throughput Nucleotide Sequencing; Humans; Laminin; Nephritis
PubMed: 33476040
DOI: 10.1007/s13730-021-00574-1 -
Pediatric Hematology and Oncology 2023Although hematopoietic stem cell transplantation (HSCT) has been widely used to treat patients with beta-thalassemia major, evidence showing whether this treatment...
Thalassemia patients in transfussion dependent period and after hematopoietic stem cell transplantation: how are the psychiatric status and life quality of these patients?
Although hematopoietic stem cell transplantation (HSCT) has been widely used to treat patients with beta-thalassemia major, evidence showing whether this treatment improves mental health, self esteem and health-related quality of life (HRQoL) is limited. We aimed to describe psychiatric problems, HRQoL and self-esteem scores of patients who have thalassemia and compared with patients who underwent HSCT in the current study. A total of 24 patients with thalassemia major and 13 patients who underwent HSCT at least 2 years ago aged between 7-37 years were included. We used The Children's Depression Inventory, The Spielberger State-Trait Anxiety Inventory, and Pediatric Quality of LifeTM (PedsQL™) for assesment of children and Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), World Health Organization Quality of Life Scale Brief Version (WHOQOL-BREF) for assessment of adults. We also used Piers Harris Self Concept Scale for children and adults. Psychopathologies are common in both groups (50% in Thalassemia group and 69.2% in HSCT group). Popularity scores in Piers Haris scale of patients in HSCT group were significantly higher compared to thalassemia group ( = 0.03). Additionally, HSCT group had higher scores in physical health subscales of HRQoL in both children and parents'( = 0.02, = 0.03 respectively). Our findings suggest improved HRQoL and self-esteem in thalassemia patients after HSCT. However, due to the high prevalence of mental disorders in both groups, we would like to emphasize that clinicians should examine not only the physical but also the psychological state of the patients with thalessemia during the their treatment and follow-up period after HSCT.
Topics: Adult; Humans; Child; Adolescent; Young Adult; Quality of Life; beta-Thalassemia; Thalassemia; Parents; Hematopoietic Stem Cell Transplantation
PubMed: 37519029
DOI: 10.1080/08880018.2023.2220733 -
European Journal of Medical Genetics May 2020Congenital microcoria (MCOR) is an eye anomaly characterized by a pupil with diameter below 2 mm, and is caused by underdevelopment or absence of the dilator muscle of...
Congenital microcoria (MCOR) is an eye anomaly characterized by a pupil with diameter below 2 mm, and is caused by underdevelopment or absence of the dilator muscle of the pupil. Two types have been described: a recessive, syndromic (Pierson syndrome OMIM 609049) and a dominant, isolated form (MCOR syndrome OMIM 156600). Fares-Taie and colleagues described inherited microdeletions in chromosome band 13q32.1 segregating with dominant microcoria in several families. The GPR180 gene is located within the smallest commonly deleted region and encodes a G protein-coupled receptor involved in smooth muscle cells growth. We here describe a patient with isolated, non-syndromic MCOR. The patient presented with a blue iris and small pupils, non-reactive to cycloplegic agents. Her mother had a milder ocular phenotype, namely a blue iris with hypoplastic crypts and mild myopia. We present a detailed clinical examination and follow up. DNA from the index patient was analyzed for the presence of chromosomal imbalances using molecular karyotyping. The genetic test revealed a small duplication of chromosome band 13q32.1. The duplication affected a 289 kb region, encompassing 11 genes including GPR180. Interestingly, the patient displays only MCOR in contrast to patients with the reciprocal deletion who present with MCOR and iridocorneal angle dysgenesis. This genetic anomaly was inherited from the mother who carries the duplication in mosaic form, which should be considered when offering genetic counselling. In summary, we describe the first 13q32.1 duplication encompassing GPR180 associated with MCOR.
Topics: Adult; Child, Preschool; Chromosome Duplication; Chromosomes, Human, Pair 13; Eye; Female; Humans; Mosaicism; Pedigree; Pupil Disorders; Receptors, G-Protein-Coupled
PubMed: 32200002
DOI: 10.1016/j.ejmg.2020.103918 -
BMJ Case Reports Jul 2020
Topics: Fatal Outcome; Humans; Infant, Newborn; Kidney Diseases, Cystic; Male; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pupil Disorders
PubMed: 32616536
DOI: 10.1136/bcr-2020-236517