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Milk protein is a key quality indicator of milk, so elucidating its synthesis mechanism has been the focus of research in recent years. Studies have shown that both miRNAs and mRNA genes play important roles in the regulation of milk protein synthesis. In this study, a total of 7 and 4073 differentially expressed miRNA and mRNA genes were identified between early and peak lactation, respectively. Overexpression and knockdown experiments of parathyroid hormone like hormone gene (PTHLH) gene showed that it can promote milk protein synthesis in buffalo mammary epithelial cells (BuMECs) through mammalian target of rapamycin (mTOR) and janus kinase 2/signal transducer and activator of transcription 5 (JAK2–STAT5) signaling pathways, and the experiments treated with miR-190a mimic or inhibitor showed that miR-190a inhibited the expression of PTHLH gene. In addition, miR-190a inhibited milk protein synthesis by targeting PTHLH through mTOR and JAK2–STAT5 signaling pathways in BuMECs. Collectively, these findings reveal a novel miR-190a–PTHLH pathway that has a significant role in regulating milk protein synthesis.

BackgroundAutosomal-dominant brachydactyly type E is a congenital abnormality characterized by small hands and feet, which is a consequence of shortened metacarpals and metatarsals. We recently encountered a young gentleman exhibiting shortening of 4th and 5th fingers and toes. Initially, we suspected him having pseudopseudohypoparathyroidism (PPHP) because of normal biochemical parameters, including electrolyte, Ca, P, and parathyroid hormone (PTH) levels; however, his mother and maternal grandmother had the same conditions in their hands and feet. Furthermore, his mother showed normal biochemical parameters. To the best of our knowledge, PPHP is inherited via a mutated paternal allele, owing to the paternal imprinting of GNAS (guanine nucleotide binding protein, alpha stimulating) in the renal proximal tubule. Therefore, we decided to further analyze the genetic background in this family.MethodsWhole exome sequencing was performed using genomic DNA from the affected mother, son, and the unaffected father as a negative control.ResultsWe selected the intersection between 45,490 variants from the mother and 45,646 variants from the son and excluded 27,512 overlapping variants identified from the father. By excluding homogenous and compound heterozygous variants and removing all previously reported variants, 147 variants were identified to be shared by the mother and son. Variants that had least proximities among species were excluded and finally 23 variants remained.ConclusionAmong them, we identified a defect in parathyroid hormone like hormone (PTHLH), encoding the PTH-related protein, to be disease-causative. Herein, we report a family affected with brachydactyly type E2 caused by a novel PTHLH mutation, which was confused with PPHP with unclassical genetic penetrance.

Parathyroid hormone like hormone (PTHLH) signaling is essential for the proper formation of bone and its elevation or disruption has been directly implicated in several different skeletal dysplasias. We report a patient with a 2.802 Mb deletion upstream of the PTHLH coding sequence who presents with multiple fractures, metaphyseal changes, and overall features consistent with hyperparathyroid like disease. Analysis of the deleted region revealed the loss of putative regulatory regions adjacent to PTHLH and the possible gain of a limb enhancer. Furthermore, PTHLH expression appeared to be mis‐regulated in fibroblasts derived from the patient. Altogether, we find that the disruption of the regulatory landscape of PTHLH likely results in its inappropriate expression and this novel clinical presentation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Differentially expressed miRNA and mRNA are screened in the mammary gland of buffalo. • PTHLH promotes milk protein synthesis through mTOR and JAK2–STAT5 signaling pathways. • The PTHLH is the target gene of miR-190a. • The miR-190a inhibits milk protein synthesis by targeting PTHLH. Milk protein is a key quality indicator of milk, so elucidating its synthesis mechanism has been the focus of research in recent years. Studies have shown that both miRNAs and mRNA genes play important roles in the regulation of milk protein synthesis. In this study, a total of 7 and 4073 differentially expressed miRNA and mRNA genes were identified between early and peak lactation, respectively. Overexpression and knockdown experiments of parathyroid hormone like hormone gene (PTHLH) gene showed that it can promote milk protein synthesis in buffalo mammary epithelial cells (BuMECs) through mammalian target of rapamycin (mTOR) and janus kinase 2/signal transducer and activator of transcription 5 (JAK2–STAT5) signaling pathways, and the experiments treated with miR-190a mimic or inhibitor showed that miR-190a inhibited the expression of PTHLH gene. In addition, miR-190a inhibited milk protein synthesis by targeting PTHLH through mTOR and JAK2–STAT5 signaling pathways in BuMECs. Collectively, these findings reveal a novel miR-190a–PTHLH pathway that has a significant role in regulating milk protein synthesis. [ABSTRACT FROM AUTHOR]

Background: Autosomal-dominant brachydactyly type E is a congenital abnormality characterized by small hands and feet, which is a consequence of shortened metacarpals and metatarsals. We recently encountered a young gentleman exhibiting shortening of 4th and 5th fingers and toes. Initially, we suspected him having pseudopseudohypoparathyroidism (PPHP) because of normal biochemical parameters, including electrolyte, Ca, P, and parathyroid hormone (PTH) levels; however, his mother and maternal grandmother had the same conditions in their hands and feet. Furthermore, his mother showed normal biochemical parameters. To the best of our knowledge, PPHP is inherited via a mutated paternal allele, owing to the paternal imprinting of GNAS (guanine nucleotide binding protein, alpha stimulating) in the renal proximal tubule. Therefore, we decided to further analyze the genetic background in this family., Methods: Whole exome sequencing was performed using genomic DNA from the affected mother, son, and the unaffected father as a negative control., Results: We selected the intersection between 45,490 variants from the mother and 45,646 variants from the son and excluded 27,512 overlapping variants identified from the father. By excluding homogenous and compound heterozygous variants and removing all previously reported variants, 147 variants were identified to be shared by the mother and son. Variants that had least proximities among species were excluded and finally 23 variants remained., Conclusion: Among them, we identified a defect in parathyroid hormone like hormone (PTHLH), encoding the PTH-related protein, to be disease-causative. Herein, we report a family affected with brachydactyly type E2 caused by a novel PTHLH mutation, which was confused with PPHP with unclassical genetic penetrance., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2018 Korean Endocrine Society.)