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Novel missense mutation affecting the LIM-A domain of LMX1B in a family with Nail-Patella syndrome.

ABSTRACT: 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.

SUBMITTER: Claverie-Martin F

PROVIDER: S-EPMC6409120 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Novel missense mutation affecting the LIM-A domain of LMX1B in a family with Nail-Patella syndrome.

Claverie-Martin Felix F Trindade Amelia A Garcia-Gonzalez Noriela C NC Callejon Alicia Callejon AC

Intractable & rare diseases research 20190201 1

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 <i>LMX1B</i> gene, which encodes the LIM homeodomain transcription fact ...[more]

PMID: 30881852

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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.

Dataset Information

Novel missense mutation affecting the LIM-A domain of LMX1B in a family with Nail-Patella syndrome.

Publications

Novel missense mutation affecting the LIM-A domain of LMX1B in a family with Nail-Patella syndrome.

Similar Datasets

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