Mutation analysis of LMX1B gene in nail-patella syndrome patients.
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ABSTRACT:
SUBMITTER: McIntosh I
PROVIDER: S-EPMC1377636 | biostudies-other | 1998 Dec
REPOSITORIES: biostudies-other
Publications
Mutation analysis of LMX1B gene in nail-patella syndrome patients.
McIntosh I I Dreyer S D SD Clough M V MV Dunston J A JA Eyaid W W Roig C M CM Montgomery T T Ala-Mello S S Kaitila I I Winterpacht A A Zabel B B Frydman M M Cole W G WG Francomano C A CA Lee B B
American journal of human genetics 19981201 6
Nail-patella syndrome (NPS), a pleiotropic disorder exhibiting autosomal dominant inheritance, has been studied for >100 years. Recent evidence shows that NPS is the result of mutations in the LIM-homeodomain gene LMX1B. To determine whether specific LMX1B mutations are associated with different aspects of the NPS phenotype, we screened a cohort of 41 NPS families for LMX1B mutations. A total of 25 mutations were identified in 37 families. The nature of the mutations supports the hypothesis that ...[more]
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Project description:PurposeTo report the clinical, ophthalmic, extraophthalmic, and genetic characteristics of nail-patella syndrome (NPS) in a Chilean family and to investigate the expressivity of open angle glaucoma (OAG) and ocular hypertension (OHT) in the family members.MethodsFive family members affected with NPS and two unaffected members underwent a complete ophthalmologic examination, including computerized visual field, optical coherence tomography (OCT) of the optic disc and ultrasound pachymetry. Renal function was assessed by urinalysis and blood tests. Orthopedic evaluations were also performed, including radiological studies of the wrist, elbow and hip joints. Genomic DNA was extracted from peripheral leukocytes of the five affected and two unaffected family members. Exons 2-6 of the LIM homeobox transcription factor 1-beta (LMX1B) gene were screened for mutations by DNA sequencing of the proband. We also screened for mutations in exon 2 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) of the other participants and 91 blood donors.ResultsFive living family members from three generations were positively diagnosed with NPS, three of them with varying degrees of OAG and one with OHT. Retinal nerve fiber layer (RNFL) thickness measured by spectral domain OCT was below normal values in three individuals. All subjects evaluated had normal nephrologic function. Orthopedic, clinical, and radiological alterations were compatible with NPS. Screening for mutations in exons 2- 6 of LMX1B showed a heterozygous missense mutation c.194 A>C changing glutamine to proline within exon 2 in codon 65 (Q65P) of the coding sequence. This mutation was present in all NPS subjects and absent in the unaffected family members and in 91 Chilean blood donors.ConclusionsThis is the first report of c.194 A>C mutation in LMX1B in a Chilean family with NPS and the second worldwide. The phenotype associated with this mutation is variable within the family, although we noted a close connection between the presence of the c.194 A>C mutation and the presence of OHT or OAG and probably also with an early onset of OHT in patients with NPS. All subjects older than 21 years had either OHT or OAG. We also suggest that the LMX1B mutation may be related to affective disorders.
| S-EPMC3154131 | biostudies-literature
Project description:Nail-patella syndrome (NPS) is a pleiotropic autosomal-dominant disorder due to mutations in the gene LMX1B. It has traditionally been characterized by a tetrad of dermatologic and musculoskeletal abnormalities. However, one of the most serious manifestations of NPS is kidney disease, which may be present in up to 40% of affected individuals. Although LMX1B is a developmental LIM-homeodomain transcription factor, it is expressed in post-natal life in the glomerular podocyte, suggesting a regulatory role in that cell. Kidney disease in NPS seems to occur more often in some families with NPS, but it does not segregate with any particular mutation type or location. Two patterns of NPS nephropathy may be distinguished. Most affected individuals manifest only an accelerated age-related loss of filtration function in comparison with unaffected individuals. Development of symptomatic kidney failure is rare in this group, and proteinuria (present in approximately one-third) does not appear to be progressive. A small minority (5-10%) of individuals with NPS develop nephrotic-range proteinuria as early as childhood or young adulthood and progress to end-stage kidney failure over variable periods of time. It is proposed that this latter group reflects the effects of more global podocyte dysfunction, possibly due to the combination of a mutation in LMX1B along with an otherwise innocuous polymorphism or mutation involving any of several genes expressed in podocytes (e.g. NPHS2, CD2AP), the transription of which is regulated by LMX1B.
| S-EPMC2770138 | biostudies-literature
Project description:Nail-patella syndrome (NPS) is an autosomal dominant disease that typically involves the nails, knees, elbows and the presence of iliac horns. In addition, some patients develop glomerulopathy or adult-onset glaucoma. NPS is caused by loss-of-function mutations in the LMX1B gene. In this study, phenotype-genotype correlation was analyzed in 9 unrelated Korean children with NPS and their affected family members. The probands included 5 boy and 4 girls who were confirmed to have NPS, as well as 6 of their affected parents. All of the patients (100%) had dysplastic nails, while 13 patients (86.7%) had patellar anomalies, 8 (53.3%) had iliac horns, 6 (40.0%) had elbow contracture, and 4 (26.7%) had nephropathy including one patient who developed end-stage renal disease at age 4.2. The genetic study revealed 8 different LMX1B mutations (5 missense mutations, 1 frame-shifting deletion and 2 abnormal splicing mutations), 6 of which were novel. Genotype-phenotype correlation was not identified, but inter- and intrafamilial phenotypic variability was observed. Overall, these findings are similar to the results of previously conducted studies, and the mechanism underlying the phenotypic variations and predisposing factors of the development and progression of nephropathy in NPS patients are still unknown.
| S-EPMC2633198 | biostudies-literature
Project description:Nail-patella syndrome (NPS) is a multi-system disorder characterized by hypoplastic nails, hypoplastic patella, skeletal deformities, and iliac horns, which is caused by heterozygous variants of LMX1B. Nephropathy ranging from mild urinary abnormality to end-stage renal disease occurs in some individuals with NPS. Because of the low prevalence of NPS and the lack of longitudinal studies of its kidney involvement, the clinical, pathological, and genetic features characterizing severe nephropathy remain unclear. We conducted a Japanese survey of NPS with nephropathy, and analyzed their clinical course, pathological features, and factors associated with severe renal phenotype. LMX1B gene analysis and luciferase reporter assay were also performed. Among 13 NPS nephropathy cases with genetic validation, 5 patients who had moderate-to-massive proteinuria progressed to advanced chronic kidney disease or end-stage renal disease. Pathological findings in the early phase did not necessarily correlate with renal prognosis. Variants associated with deteriorated renal function including a novel variants were confined to the N-terminal region of the LIM domain and a short sequence in the LMX1B homeodomain, which were distinct from reported variants found in isolated nephropathy without extrarenal manifestation (LMX1B-associated nephropathy). Luciferase reporter analysis demonstrated that variants in patients with severe renal phenotype caused haploinsufficiency, but no dominant-negative effects on promoter activation. A distinct proportion of NPS nephropathy patients progressed to end-stage renal disease in adolescence or young adulthood. Patients with moderate or severe proteinuria, especially those with variants in specific regions of LMX1B, should be monitored for potential deterioration of renal function.
| S-EPMC7608088 | biostudies-literature
Project description:PurposeTo describe the genetic and clinical findings in a large Spanish pedigree with nail-patella syndrome (NPS) and to investigate the expressivity of open angle glaucoma (OAG) in the family members.MethodsAll individuals underwent a complete ophthalmologic examination, including optical coherence tomography (OCT) of the optic disc and peripapillary region and ultrasound pachymetry. Screening for mutations in the LMX1B gene was performed by denaturing gradient gel electrophoresis and direct genomic sequencing analysis.ResultsTen family members had NPS, seven with varying degrees of ocular hypertension (OHT). Only one of these had advanced OAG. The others showed high pachymetry values and OCT retinal nerve fiber layer (RNFL) thickness above the normal values. Screening for mutations in the exonic and flanking sequences of the LMX1B gene showed a deletion of one G (289delG) within the coding sequence of exon 3 at codon 97, resulting in a frame shift that creates a premature stop at codon 105 (E97fsX105), predicting a truncated protein. This mutation was present in all NPS patients and absent in the unaffected family members.ConclusionsA novel mutation in the homeobox transcription factor LMX1B causes NPS in a family with variable expressivity of the syndrome, including OAG. The pathogenic mechanism resulting from the mutation is presumably haploinsufficiency rather than a dominant negative effect, which would explain the clinical variability in this family. All NPS OHT patients had considerably thick corneas and RNFL.
| S-EPMC2669506 | biostudies-literature
Project description:Nail-patella syndrome, also known as hereditary onycho-osteodystrophy, is a rare autosomal dominant disorder with pleiotropic phenotypic expression.The present report is of a nail-patella syndrome patient, a 26-year-old female, admitted to our NeuroMuscular Rehabilitation Clinic Division for neurological symptoms, secondary to a severe spondylolysthesis with bilateral L5 pedicle fracture. During hospitalization, she was also diagnosed with mild thyrotoxicosis, but interestingly enough, the bone mineral density, assessed at multiple sites, was quasi-normal.
| S-EPMC3307073 | biostudies-literature
Project description:The Nail Patella Syndrome (NPS) is an autosomal dominant connective tissue disorder affecting the nails, skeletal system, kidneys and eyes. Here, we report a case of NPS detected at 19 weeks of gestation. The movements of the elbow and knee joints were restricted and there was rotational deformity of the knee joints. To our knowledge, this is the first report of in-utero restriction of limb movements in a fetus with NPS.
| S-EPMC5644329 | biostudies-literature
Project description:We describe here an interesting case of a 7-day-old male infant brought with parental concerns of inability to extend both knees. Clinical evaluation revealed dysplastic fingernails, bilateral abnormal patellae, triangular lunules in conjunction with pathognomic iliac horns on pelvic radiographs suggesting the possibility of nail-patella syndrome (NPS). Other competing diagnoses with similar phenotypic features were considered and sequentially excluded. A definitive diagnosis was established by the identification of the principal mutation at the LMX1B gene locus of chromosome 9. NPS is seldom diagnosed in neonates due to the heterogeneity of clinical presentations as well as the subtlety of clinical clues in this population. NPS is a dominantly inherited disorder that is predominantly familial in origin and thus carries important implications for the prenatal diagnosis of future pregnancies as well as pre-emptive surveillance of nephropathy in the index child.
| S-EPMC7949362 | biostudies-literature
Project description:Nail-patella syndrome (NPS) is a rare autosomal dominant disease characterized by developmental defects of dorsal limb structures, the kidney, and the eye, that manifest as dysplastic nails, hypoplastic or absent patella, elbow dysplasia, iliac horns, glomerulopathy, and adult-onset glaucoma, respectively. This disorder is inherited in an autosomal dominant mode and is caused by heterozygous loss-of-function mutations in the LMX1B gene, which encodes the LIM homeodomain transcription factor LMX1B. In this study, we report the clinical findings of a Spanish family, from the Canary Islands, with three affected members who displayed varying phenotypes. DNA sequence analysis identified a novel heterozygous missense mutation in LMX1B, c.305A>G, p.(Y102C), that segregated with the disease. The tyrosine residue affected by the mutation is highly conserved in evolution, and is located in the LIM-A domain, next to one of the cysteine residues involved in zinc binding, suggesting that p.(Y102C) affects LMX1B function by disturbing its interactions with other proteins. Our results expand the mutation spectrum of LMX1B and provide insight into the molecular mechanisms of NPS pathology.
| S-EPMC6409120 | biostudies-literature
Project description:BackgroundNail-patella syndrome (NPS) is an autosomal dominant disorder caused by mutations in the LMX1B gene and is characterized by nail dysplasia, skeletal abnormalities, and nephropathy. We herein report a case of steroid-resistant nephrotic syndrome (SRNS) prior to overt orthopedic symptoms in a patient with NPS.Case presentationA 24-year-old woman presented to our hospital with knee pain. She had poorly developed nails, hypoplastic patellas, dislocation of the elbows, and iliac horns in the pelvis. At the age of 7, she developed nephrotic syndrome and was diagnosed with primary focal segmental glomerulosclerosis by renal biopsy. She received long-term corticosteroid therapy with no obvious response. Her clinical course and orthopedic manifestations indicated NPS, and a genetic analysis showed a de novo mutation in the LMX1B gene (c.819 + 1G > A). Nephropathy in this case was considered to be associated with NPS. Therefore, we discontinued corticosteroids without the exacerbation of nephrotic syndrome.ConclusionsPatients with NPS may develop nephrotic syndrome prior to overt orthopedic symptoms and only show non-specific findings in renal biopsy at an early stage of NPS nephropathy. Hereditary nephrotic syndrome, often presenting as childhood-onset SRNS, may also be difficult to diagnose in patients with the following conditions: renal symptoms prior to overt extrarenal symptoms, de novo mutations, and non-specific findings in renal biopsy. Therefore, in the management of SRNS in children, we need to reconsider the possibility of hereditary diseases such as NPS even without a family history.
| S-EPMC5363042 | biostudies-literature