An Expanding Universe of FSGS Genes and Phenotypes

Kopp, Jeffrey B.

doi:10.1681/asn.2013060661

Cited by 12 publications

(9 citation statements)

References 12 publications

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“…Interestingly, detailed immunohistological analysis of a renal biopsy of a 6-year-old child with LMX1B nephropathy (where light microscopy showed normal glomeruli and no abnormalities of the GBM) revealed a cytoplasmic granular staining pattern for CD2AP, rather than a linear staining pattern seen in control samples [ 8 ]. In light of these reports, LMX1B, therefore, becomes a candidate gene for non-syndromic autosomal dominant FSGS [ 27 ] and autosomal-dominant forms of minimal change disease.…”

Section: Discussionmentioning

confidence: 99%

A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause'

Edwards

Rice

Raman

et al. 2014

Clinical Kidney Journal

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End-stage renal disease (ESRD) presenting in a familial autosomal dominant pattern points to an underlying monogenic cause. Nail-patella syndrome (NPS) is an autosomal dominant disorder that may lead to ESRD caused by mutations in the transcription factor LMX1B. Renal-limited forms of this disease, termed nail-patella-like renal disease (NPLRD), and LMX1B nephropathy have recently been described. We report a large family, from the North East of England, with seven affected members with varying phenotypes of renal disease, ranging from ESRD at 28 years of age to microscopic haematuria and proteinuria and relatively preserved renal function. In this family, there were no extra-renal manifestations to suggest NPS. Genome-wide linkage studies and inheritance by descent (IBD) suggested disease loci on Chromosome 1 and 9. Whole exome sequencing (WES) analysis identified a novel sequence variant (p.R249Q) in the LMX1B gene in each of the three samples submitted, which was confirmed using Sanger sequencing. The variant segregated with the disease in all affected individuals. In silico modelling revealed that R249 is putatively located in close proximity to the DNA phosphoskeleton, supporting a role for this residue in the interaction between the LMX1B homeodomain and its target DNA. WES and analysis of potential target genes, including CD2AP, NPHS2, COL4A3, COL4A4 and COL4A5, did not reveal any co-inherited pathogenic variants. In conclusion, we confirm a novel LMX1B mutation in a large family with an autosomal dominant pattern of nephropathy. This report confirms that LMX1B mutations may cause a glomerulopathy without extra-renal manifestations. A molecular genetic diagnosis of LMX1B nephropathy thus provides a definitive diagnosis, prevents the need for renal biopsies and allows at risk family members to be screened.

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Section: Discussionmentioning

confidence: 99%

A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause'

Edwards

Rice

Raman

et al. 2014

Clinical Kidney Journal

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“…23 Although the term hypertensive nephrosclerosis has been used to denote this form of renal impairment, the usefulness of this term has been questioned as in many cases intrinsic renal disease takes primacy over hypertension. 24,25 One of the functional characteristics of the aging kidney is a disturbed ability to adapt to changes in sodium intake. For instance, after a sudden reduction in dietary salt, older people need more time to attain a new balance during which they lose more sodium than younger individuals.…”

Section: Pathophysiology Of Bp Regulation In the Oldest Oldmentioning

confidence: 99%

Treatment of Hypertension in the Oldest Old

et al. 2014

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A n 88-year-old woman with chronic hypertension was seen in the internal/geriatric medicine outpatient clinic. She had been treated for high blood pressure (BP) for ≈20 years with a low-dose thiazide, to which an angiotensin-converting enzyme-inhibitor had been added 5 years ago. In addition, after a possible transient ischemic attack 10 years ago, aspirin, omeprazole, and simvastatin had been added. She is known with mild cognitive impairment, which is stable with a mini-mental state examination score of 25, and a mild depression for which fluoxetine has been prescribed. In addition, she experienced 2 falls in the past 2 years; calcium/vitamin D and alendronate were started for the management of osteoporosis. On physical examination, she appears vital with a normal fluent gait and no signs of hemiparesis. Her BP is 165/75 mm Hg in the sitting position. Immediately after standing up from her chair, she feels dizzy for ≈10 seconds, but after 1 and 3 minutes, no orthostatic hypotension is found. Estimated glomerular filtration rate is 50 mL/min per 1.73 m 2 . Should antihypertensive treatment be intensified, left unaltered, or reduced?The oldest old, that is, persons aged ≥80 years, will be the fastest growing segment of the population for the next 40 years. By 2050, more than one quarter of all men and women aged ≥65 years in the Western world will be in the oldest old group. 1Despite longer life expectancy, the prevalence of various chronic diseases and functional impairment increases with age. As a result, populations of older individuals are often highly heterogeneous and individuals with same chronological age vary widely in health and functional ability. In other words, there is substantial heterogeneity in their biological age, and those at the higher end of biological age are often referred to as vulnerable or frail.BP rises with age, and ≈80% of people in Western societies aged ≥80 years have hypertension.2 Their hypertension is commonly characterized by elevated systolic BP, with often normal or even low diastolic BP. The widened pulse pressure (PP) is a reflection of increased arterial stiffness. Despite the large body of evidence in middle-aged populations, the predictive value of high BP in this rapidly growing older population is still debated, as is the question of whether hypertension should be treated, and if so, how intensively. Importantly, the current paradigm of lower is better may not apply to (untreated or treated) BP in the oldest old.In this concise narrative review, we summarize evidence from observational studies and randomized clinical trials. We conclude that biological age/frailty is becoming an important criterion for treatment decisions. Finally, we address what we think are the most pressing research questions for the coming years. Pathophysiology of BP Regulation in the Oldest OldAlthough hypertension in the oldest old may reflect a longstanding condition, often it manifests itself as a de novo abnormality. Data from the Framingham Heart Study indicate that the majority of patient...

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“…The secondary disease is mainly caused by various pathogen infections, such as toxoplasma, syphilis, rubella virus, cytomegalovirus, and herpes simplex virus [1, 2]. The majority of patients with CNS show mutations in genes encoding key podocyte proteins that constitute the slit diaphragm ( NPHS1 and NPHS2 ); others are expressed in the podocyte membrane (PLCE1 ), mitochondria, ( COQ6 , COQ2 ) or glomerular basement membrane (LAMB2 ), and other genes encode transcription factors that are necessary for normal development ( WT1 , LMX1B ) [2–11]. NPHS1 and NPHS2 mutations are the main causes of CNS, but LAMB2 and WT1 mutations have been detected in a few CNS patients in Europe and America [3, 12].…”

Section: Introductionmentioning

confidence: 99%

Gene mutation analysis in 12 Chinese children with congenital nephrotic syndrome

Cao

Shen

et al. 2018

BMC Nephrol

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BackgroundCongenital nephrotic syndrome (CNS) is characterised by increased proteinuria, hypoproteinemia, and edema beginning in the first 3 months of life. Recently, molecular genetic studies have identified several genes involved in the pathogenesis of CNS. A systematic investigation of the genes for CNS in China has never been performed; therefore, we conducted a mutational analysis in 12 children with CNS,with the children coming from 10 provinces and autonomous regions in China.MethodsTwelve children with CNS were enrolled from 2009 to 2016. A mutational analysis was performed in six children by Sanger sequencing in eight genes (NPHS1, NPHS2, PLCE1, WT1, LAMB2, LMXIB, COQ6 and COQ2) before 2014, and whole-exome sequencing was used from 2014 to 2016 in another six children. Significant variants that were detected by next generation sequencing were confirmed by conventional Sanger sequencing in the patients’ families.ResultsOf the 12 children, eight patients had a compound heterozygous NPHS1 mutation, one patient had a de novo mutation in the WT1 gene, and another patient with extrarenal symptoms had a homozygous mutation in the COQ6 gene. No mutations were detected in genes NPHS2, PLCE1, LAMB2, LMXIB, and COQ2 in the 12 patients.ConclusionsThis study demonstrates that the majority of CNS cases (67%, 8/12 patients) are caused by genetic defects, and the NPHS1 mutation is the most common cause of CNS in Chinese patients. A mutational analysis of NPHS1 should be recommended in Chinese patients with CNS in all exons of NPHS1 and in the intron-exon boundaries.

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An Expanding Universe of FSGS Genes and Phenotypes

Cited by 12 publications

References 12 publications

A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause'

A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause'

Treatment of Hypertension in the Oldest Old

Gene mutation analysis in 12 Chinese children with congenital nephrotic syndrome

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