Qing Fang

Shanghai Children's Medical Center

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Sally A. Camper

University of Michigan–Ann Arbor

Qianyi Ma

University of Science and Technology Beijing

Luciani R. Carvalho

Universidade de São Paulo

Berenice B. Mendonça

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

Ivo J.P. Arnhold

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

Jun Z. Li

University of Michigan–Ann Arbor

Alexander A.L. Jorge

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

David F. Dolan

University of Michigan–Ann Arbor

Péter Gergics

Universidade de São Paulo

Ayse Bilge Ozel

University of Michigan–Ann Arbor

Cooperative Institutions

University of Michigan–Ann Arbor

Universidade de São Paulo

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

Regeneron (United States)

Capital Medical University

Peking University

Shanghai Jiao Tong University

Wuhan University

Harvard University

Sichuan University

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The 133-kDa N-terminal domain enables myosin 15 to maintain mechanotransducing stereocilia and is essential for hearing

eLife (2015)

Qing Fang Artur A. Indzhykulian Mirna Mustapha Gavin P. Riordan David F. Dolan

The precise assembly of inner ear hair cell stereocilia into rows of increasing height is critical for mechanotransduction and the sense of hearing. Yet, how the lengths of actin-based stereocilia are regulated remains poorly understood. Mutations of the molecular motor myosin 15 stunt stereocilia growth and cause deafness. We found that hair cells express two isoforms of myosin 15 that differ by inclusion of an 133-kDa N-terminal domain, and that these isoforms can selectively traffic to different stereocilia rows. Using an isoform-specific knockout mouse, we show that hair cells expressing only the small isoform remarkably develop normal stereocilia bundles. However, a critical subset of stereocilia with active mechanotransducer channels subsequently retracts. The larger isoform with the 133-kDa N-terminal domain traffics to these specialized stereocilia and prevents disassembly of their actin core. Our results show that myosin 15 isoforms can navigate between functionally distinct classes of stereocilia, and are independently required to assemble and then maintain the intricate hair bundle architecture.

Stereocilia (inner ear)

Kinocilium

Mechanotransduction

10.7554/elife.08627

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Citations (85)

Deafness and Permanently Reduced Potassium Channel Gene Expression and Function in HypothyroidPit1^dwMutants

Journal of Neuroscience (2009)

Mirna Mustapha Qing Fang Tzy-Wen Gong David F. Dolan Yehoash Raphael

The absence of thyroid hormone (TH) during late gestation and early infancy can cause irreparable deafness in both humans and rodents. A variety of rodent models have been used in an effort to identify the underlying molecular mechanism. Here, we characterize a mouse model of secondary hypothyroidism, pituitary transcription factor 1 ( Pit1 dw ), which has profound, congenital deafness that is rescued by oral TH replacement. These mutants have tectorial membrane abnormalities, including a prominent Hensen's stripe, elevated β-tectorin composition, and disrupted striated-sheet matrix. They lack distortion product otoacoustic emissions and cochlear microphonic responses, and exhibit reduced endocochlear potentials, suggesting defects in outer hair cell function and potassium recycling. Auditory system and hair cell physiology, histology, and anatomy studies reveal novel defects of hormone deficiency related to deafness: (1) permanently impaired expression of KCNJ10 in the stria vascularis of Pit1 dw mice, which likely contributes to the reduced endocochlear potential, (2) significant outer hair cell loss in the mutants, which may result from cellular stress induced by the lower KCNQ4 expression and current levels in Pit1 dw mutant outer hair cells, and (3) sensory and strial cell deterioration, which may have implications for thyroid hormone dysregulation in age-related hearing impairment. In summary, we suggest that these defects in outer hair cell and strial cell function are important contributors to the hearing impairment in Pit1 dw mice.

Endocochlear potential

10.1523/jneurosci.4957-08.2009

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Citations (69)

Functional analysis of a novel pathogenic variant in CREBBP associated with bone development

Pediatric Research (2024)

Qing Fang Yunlan Xu Jue Feng Xiaoqing Zhang Bo Wang

10.1038/s41390-024-03490-z

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Citations (0)

Growth hormone deficiency with advanced bone age: phenotypic interaction between GHRH receptor and CYP21A2 mutations diagnosed by sanger and whole exome sequencing

Archives of Endocrinology and Metabolism (2017)

Fernanda A. Correa Marcela M. França Qing Fang Qianyi Ma Tânia A.S.S. Bachega

Isolated growth hormone deficiency (IGHD) is the most common pituitary hormone deficiency and, clinically, patients have delayed bone age. High sequence similarity between CYP21A2 gene and CYP21A1P pseudogene poses difficulties for exome sequencing interpretation. A 7.5 year-old boy born to second-degree cousins presented with severe short stature (height SDS -3.7) and bone age of 6 years. Clonidine and combined pituitary stimulation tests revealed GH deficiency. Pituitary MRI was normal. The patient was successfully treated with rGH. Surprisingly, at 10.8 years, his bone age had advanced to 13 years, but physical exam, LH and testosterone levels remained prepubertal. An ACTH stimulation test disclosed a non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency explaining the bone age advancement and, therefore, treatment with cortisone acetate was added. The genetic diagnosis of a homozygous mutation in GHRHR (p.Leu144His), a homozygous CYP21A2 mutation (p.Val282Leu) and CYP21A1P pseudogene duplication was established by Sanger sequencing, MLPA and whole-exome sequencing. We report the unusual clinical presentation of a patient born to consanguineous parents with two recessive endocrine diseases: non-classic congenital adrenal hyperplasia modifying the classical GH deficiency phenotype. We used a method of paired read mapping aided by neighbouring mis-matches to overcome the challenges of exome-sequencing in the presence of a pseudogene.

Sanger sequencing

IGHD

Exome

10.1590/2359-3997000000311

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Citations (6)

Modulation effects of repetitive transcranial magnetic stimulation on target and indirect target nodes in patients with major depressive disorder

Journal of Psychiatric Research (2024)

Jiayu Pan Keming Ren Jiashu Yao Jiangwei Chen Qing Fang

Modulation (music)

10.1016/j.jpsychires.2024.10.012

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Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum

Genes (2021)

Marilena Nakaguma Nathalia Garcia Bianchi Pereira Ferreira Anna Benedetti Mariana Cotarelli Madi Juliana Moreira Silva

We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.

IGHD

Penetrance

10.3390/genes12081128

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Citations (0)

HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype

Clinical Endocrinology (2016)

Qing Fang Anna Benedetti Qianyi Ma Louise Gregory Jun Z. Li

Summary Introduction Mutations in the transcription factor HESX 1 can cause isolated growth hormone deficiency ( IGHD ) or combined pituitary hormone deficiency ( CPHD ) with or without septo‐optic dysplasia ( SOD ). So far there is no clear genotype–phenotype correlation. Patients and Results We report four different recessive loss‐of‐function mutations in three unrelated families with CPHD and no midline defects or SOD . A homozygous p.R160C mutation was found by Sanger sequencing in two siblings from a consanguineous family. These patients presented with ACTH , TSH and GH deficiencies, severe anterior pituitary hypoplasia ( APH ) or pituitary aplasia ( PA ) and normal posterior pituitary. The p.R160C mutation was previously reported in a case with SOD , CPHD and ectopic posterior pituitary ( EPP ). Using exome sequencing, a homozygous p.I26T mutation was found in a Brazilian patient born to consanguineous parents. This patient had evolving CPHD , normal ACTH , APH and normal posterior pituitary ( NPP ). A previously reported patient homozygous for p.I26T had evolving CPHD and EPP . Finally, we identified compound heterozygous mutations in HESX 1 , p.[R159W];[R160H], in a patient with PA and CPHD . We showed that both of these mutations abrogate the ability of HESX 1 to repress PROP 1‐mediated transcriptional activation. A patient homozygous for p.R160H was previously reported in a patient with CPHD , EPP , APH . Conclusion These three examples demonstrate that HESX 1 mutations cause variable clinical features in patients, which suggests an influence of modifier genes or environmental factors on the phenotype.

IGHD

Sanger sequencing

Compound heterozygosity

10.1111/cen.13067

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Citations (27)

Polystyrene microplastics induce male reproductive toxicity in mice by activating spermatogonium mitochondrial oxidative stress and apoptosis

Chemico-Biological Interactions (2024)

Qing Fang Chenyang Wang Ying Xiong

Reproductive toxicity

10.1016/j.cbi.2024.111043

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Citations (10)

Aquaporin 4-Mediated Glutamate-Induced Astrocyte Swelling Is Partially Mediated through Metabotropic Glutamate Receptor 5 Activation

Frontiers in Cellular Neuroscience (2017)

Zhongfang Shi Wei Zhang Yang Lü Yi Lu Lixin Xu

Astrocytes are one of the most abundant cell types in the mammalian central nervous system, and astrocyte swelling is the primary event associated with brain edema. Glutamate, the principal excitatory amino acid neurotransmitter in the central nervous system, is released at high levels after brain injury including cerebral ischemia. This leads to astrocyte swelling, which we previously demonstrated is related to metabotropic glutamate receptor (mGluR) activation. Aquaporin 4 (AQP4), the predominant water channel in the brain, is expressed in astrocyte endfeet and plays an important role in brain edema following ischemia. Studies recently showed that mGluR5 is also expressed on astrocytes. Therefore, it is worth investigating whether AQP4 mediates the glutamate-induced swelling of astrocytes via mGluR5. In the present study, we found that 1 mM glutamate induced cell swelling, quantified by the cell perimeter, but it had no effect on rat astrocyte viability measured by the cell counting kit-8 and lactate dehydrogenase assays. Quantitative reverse transcription polymerase chain reaction analyses revealed that AQP4, among AQP1, 4, 5, 9, and 11, was the main molecular expressed in cultured astrocytes. Glutamate-induced cell swelling was accompanied by a concentration-dependent change in AQP4 expression. Furthermore, RNAi technology revealed that AQP4 gene silencing inhibited glutamate-induced astrocyte swelling. Moreover, we found that mGluR5 expression was greatest among the other mGluRs in cultured astrocytes and was co-expressed with AQP4. Activation of mGluR5 in cultured astrocytes using (S)-3,5-dihydroxyphenylglycine (DHPG), an mGluR5 agonist, mimicked the effect of glutamate. This effect was abolished by co-incubation with the mGluR5 antagonist fenobam but was not influenced by DL-threo-β-benzyloxyaspartic acid (DL-TBOA), a glutamate transporter inhibitor. Finally, experiments in a rat model of transient middle cerebral artery occlusion revealed that co-expression of mGluR5 and AQP4 was increased in astrocyte endfeet around capillaries in the penumbra, and this was accompanied by brain edema. Collectively, these results suggest that glutamate induces cell swelling and alters AQP4 expression in astrocytes via mGluR5 activation, which may provide a novel approach for the treatment of edema following brain injury.

Aquaporin 4

10.3389/fncel.2017.00116

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Citations (48)

Oxymatrine alleviates high-fat diet/streptozotocin-induced non-alcoholic fatty liver disease in C57BL/6 J mice by modulating oxidative stress, inflammation and fibrosis

Biomedicine & Pharmacotherapy (2024)

Di Lou Qing Fang Yinghao He Ruyu Ma Xinyan Wang

Non-alcoholic fatty liver disease (NAFLD) represents a complex complication of type 2 diabetes mellitus (T2DM). Oxymatrine (OMT) is an alkaloid extracted from Sophora flavescens with broad pharmacological effects. However, there is currently a lack of research on OMT in the field of NAFLD. The present study aimed to explore the effects and underlying mechanisms of oxymatrine in treating T2DM with NAFLD. The T2DM mice model was induced by high-fat diet (HFD) combined with streptozotocin (STZ) injection in male C57BL/6 J mice. Animals were randomly divided into four groups (n = 8): Control group, DC group, OMT-L group (45 mg/kg i.g.), and OMT-H group (90 mg/kg, i.g.). The drug was administered once a day for 8 weeks. In addition, HepG2 hepatocytes were incubated with palmitic acid (PA) to establish a fatty liver cell model. Treated with OMT, the body weight and fasting blood glucose (FBG) of DC mice were reduced and the liver organ coefficient was significantly optimized. Meanwhile, OMT markedly enhanced the activities of key antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and also reduced malondialdehyde (MDA) levels. These biochemical alterations were accompanied by noticeable improvements in liver histopathology. Furthermore, OMT down-regulated the expression of NOD-like receptor protein 3 (NLRP3), interleukin-1β (IL-1β), transforming growth factor-β1 (TGF-β1) and collagen I significantly, highlighting its potential in modulating inflammatory and fibrotic pathways. In conclusion, OMT improved liver impairment effectively in diabetic mice by suppressing oxidative stress, inflammation and fibrosis. These results suggest that OMT may represent a novel therapy for NAFLD with diabetes.

Oxymatrine

Malondialdehyde

10.1016/j.biopha.2024.116491

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Citations (2)