Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity

LMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly in mice, Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one functional allele of Lmx1b appears adequate for development, Lmx1b null mice display ventral-ventral distal limbs with abnormal kidney, eye and cerebellar development, more disruptive, but fully concordant with NPS. In Lmx1b functional knockouts (KOs), Lmx1b transcription in the limb is decreased nearly 6-fold, indicating autoregulation. Herein, we report on two conserved Lmx1b-associated cis-regulatory modules (LARM1 and LARM2) that are bound by Lmx1b, amplify Lmx1b expression with unique spatial modularity in the limb, and are necessary for Lmx1b-mediated limb dorsalization. These enhancers, being conserved across vertebrates (including coelacanth, but not other fish species), and required for normal locomotion, provide a unique opportunity to study the role of dorsalization in the fin to limb transition. We also report on two NPS patient families with normal LMX1B coding sequence, but with loss-of-function variations in the LARM1/2 region, stressing the role of regulatory modules in disease pathogenesis.

Identification of limb-specific Lmx1b auto-regulatory modules with Nail-Patella Syndrome pathogenicity

LMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly, in mice Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one functional allele of murine Lmx1b appears adequate for development, Lmx1b null mice display ventral-ventral distal limbs with abnormal kidney, eye and cerebellar development, more disruptive, but fully concordant with NPS. Interestingly, in Lmx1b functional knockouts (KOs), Lmx1b transcription in the limb is decreased nearly 6-fold indicating autoregulation. Herein, we report on two conserved Lmx1b-associated cis-regulatory modules (LARM1 and LARM2) that are bound by Lmx1b, amplify Lmx1b expression in the limb and are necessary for Lmx1b-mediated limb dorsalization. Remarkably, we also report on two NPS patient families with normal LMX1B coding sequence, but loss-of-function variations in the LARM1/2 region, stressing the role of regulatory modules in disease pathogenesis.

First Report of a Known Pathogenic Variant in the FZD6 Gene, in an Iranian Family with Recessive Nail Dysplasia: A Case Re-port

Congenital Nail abnormalities are rare ectodermal defects. Autosomal recessive nail dysplasia is much rarer. Recently it has been recognized as a condition resulting in nail dystrophy in the absence of other cutaneous or extracutaneous disorders. Few case reports have identified mutations in the Frizzled 6 (FZD6) gene in families presenting with abnormal nails consistent with Non-Syndromic Congenital Nail Dysplasia. We report a family presenting, they lived in Namin a country of the Ardabil Province, northwestern Iran in 2016, for the first time in Iran in whom we identified mutations in FZD6 with abnormal nails formation.

Consecutive successful pregnancies of a patient with nail-patella syndrome

Nail-patella syndrome is a genetic disorder with some characteristic features (nail dysplasia, patellar hypoplasia, elbow dysplasia, iliac horns and renal symptoms). Renal involvement of these patients requires close follow-up in pregnancy to avoid complications like preeclampsia. In this report, we have presented two consecutive successful pregnancies of a patient with nail-patella syndrome. The first pregnancy resulted with a newborn with nail-patella syndrome and the second pregnancy resulted in a healthy newborn without any obstetric complications. Renal functions were closely followed-up during both pregnancies, and basal renal functions were normal in the pregestational period, which seems to be the most important predictor of obstetric hypertensive complications. Prenatal diagnosis of nail-patella disease is also challenging due to several possible mutations and a wide range of phenotypes of the disease. Ultrasonographic examination findings may be suspicious for the disease in the fetus like patellar hypoplasia or joint contractures.

Neurophysiology (EMG)

Background: Nail-patella syndrome (NPS) is an inherited autosomal dominant disease, with an incidence of approximately 1 in 50,000. It ischaracterized by nail dysplasia, hypoplastic patellae, other bone deformities and open angle glaucoma. The phenotype is variable. Methods: Case report Results: A 66 year old male presented with complaints of mild loss of sensation in both feet with gradual proximal spread to his knees over the past decade. There was no history of pain, paresthesias, autonomic dysfunction or weakness. Examination showed pectus excavatum with symmetrically dystrophic fingernails. Sensation to crude touch, pain and temperature were reduced up to mid shin, and vibration sense was diminished till the malleoli symmetrically. Electrophysiologic studies revealed a mild to moderate length-dependent polyneuropathy of axonal type. Detailed blood screening studies were negative. Genetic testing revealed the diagnosis of nail-patella syndrome with LMX1B gene mutation on chromosome 9q34. The lack of an identifiable acquired cause and the symmetric, slowly progressive and “painless” nature of the patient’s peripheral neuropathy point toward an inherited etiology. Conclusion: We present a case of slowly progressive sensorimotor axonal polyneuropathy in a patient with a diagnosis of NPS, which has not been previously reported. Peripheral nervous system disorder may be a variable phenotypic manifestation of LMX1B gene mutation.