Huda Zoghbi was born inBeirut, Lebanon in 20 June 1954, and raised in Beirut. She loved reading works byWilliam Shakespeare,Jane Austen andWilliam Wordsworth in high school and intended to pursueliterature at university.[8] Her mother convinced her to studybiology instead, on the grounds that 'a woman growing up in the Middle East should pick a career ensuring independence and security, while she can always write on the side'.[11][8] Zoghbi was admitted as abiological sciences major at theAmerican University of Beirut (AUB) in 1973 and entered the university'smedical school 2 years later.[8]
TheLebanese Civil War began in 1976 during her first year of medical school. Although she and her classmates decided to stay at the university, after her brother was injured by shrapnel, their parents sent them to live with their sister inAustin, Texas, with plans to return the following summer.[8][12] The war, however, raged on, and Zoghbi was under the impression that school terms at American medical schools began in October, as was the case with Lebanese schools. However, in October, it was confirmed that she was still unable to return to Lebanon due to the war, and US medical schools had begun their fall term 2 months earlier. Her family friends in America suggested she apply toVanderbilt University. Vanderbilt did not accept transfer students, but recommendedMeharry Medical College instead; Meharry accepted her on the spot.[12] Despite her continued desire to return to Lebanon the next summer, on the advice of professors at AUB, she stayed at Meharry and earned anMD degree in 1979, after which she joined theTexas Children's Hospital at theBaylor College of Medicine as apediatric resident.[8]
Zoghbi initially intended to specialise in pediatriccardiology. During her rotation at pediatricneurology, Marvin Fishman, the head of the division, convinced her that thebrain was more interesting than the heart. She then started a 3-year term as apostdoctoral researcher in pediatric neurology after she finished her residency in 1982.
Huda Zoghbi, Kavli Prize Laureate, interviews at Munch Museum, Oslo, Norway. Photo: Thomas Eckhoff
From 1982 to 1985, Zoghbi was apostdoctoral researcher in pediatric neurology at theBaylor College of Medicine. She became an assistant professor at the Department of Pediatrics at Baylor in 1988, and was successively promoted to associate professor in 1991 and professor in 1994.[13] At present, Zoghbi is a professor at the Department ofMolecular andHuman Genetics at Baylor, with appointments as a professor at the Department ofNeuroscience and the Department ofPediatrics Section of Neurology and Developmental Neuroscience, theRalph Feigin, M.D. Endowed Chair, the director of theTexas Children's Hospital Jan and Dan Duncan Neurological Research Institute, a member of the Dan L. Duncan Comprehensive Cancer Center at Baylor, and an investigator at theHoward Hughes Medical Institute.[5] She is also a member of the board of directors ofRegeneron Pharmaceuticals.[1] She also served on the Life Sciences jury for theInfosys Prize in 2014.
In 1983, Zoghbi learnt ofRett syndrome from Bengt Hagberg's account inAnnals of Neurology. The paper allowed Zoghbi to diagnose a five-year-old she treated atTexas Children's Hospital, and a week later she saw another patient with the same set of symptoms. When she investigated medical records, she found more cases of Rett syndrome that had been misdiagnosed. This sparked her interest in Rett syndrome, at a time when there was no report of the disease in the US.[3] An article she published in 1985[14] attracted many Rett syndrome patients to Texas Children's Hospital, giving her access to a large number of cases.[15]
Since most patients of Rett syndrome were girls, and symptoms were very consistent across patients, Zoghbi believedgenetics were involved in the disease process.[3] This led her to joinArthur Beaudet's group in 1985, after finishing her term as apostdoctoral researcher, for training in genetics andmolecular biology.[12] Beaudet advised against Rett syndrome as her research project since its mode of inheritance was still not obvious, and recommended a more approachable problem –spinocerebellar ataxia type 1, adominantly inherited neurological disorder. In 1988, Zoghbi left Beaudet's group and founded her own lab at Baylor.[8] In addition to her research on spinocerebellar ataxia type 1 and Rett syndrome, Zoghbi is participating in a joint research collaboration intoCDKL5 Deficiency Disorder, funded by the Loulou Foundation, Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (NRI) atTexas Children's Hospital[16]
Following the establishment of her own lab, Zoghbi continued studyingspinocerebellar ataxia type 1 (SCA1), in collaboration with Harry Orr from theUniversity of Minnesota.[17] On the same day, 8 April 1993, both Zoghbi and Orr identifiedATXN1 as the gene responsible for SCA1.[12] They determined that the disease was caused by anexpansion of theglutamine-encoding CAG trinucleotide repeat in this gene, and that the younger the age of onset, the longer the CAG repeat.[18] Further work by Zoghbi, Orr and their teams demonstrated that themisfolding, aggregation, andproteasomaldegradation of theprotein product of this gene,Ataxin 1, played a role in the disorder.[19]
After solving theetiology ofspinocerebellar ataxia type 1, Zoghbi began studying animal genes related tobalance. As Baylor'sHugo J. Bellen described the role of theatonal gene in balance infruit flies, Zoghbi chose to study itsmammalianhomolog. A member of her lab successfully cloned the mouse homolog,Math1, in 1996.[20] Her team went on to find that, in addition to its involvement in balance and coordination,Math1 is also crucial to hearing,[21] the formation of secretory cells in the gut.,[22] and neonatal respiratory rhythm and chemosensitivity in the adult brain by regulating the development of a group of hindbrain neurons.[23] Her lab has also shown that aberrant activation ofMath1 could lead tomedulloblastoma, a common childhood brain tumor, and that mice which did not expressMath1, did not develop the tumor.[24]
Ever since Zoghbi was introduced toRett syndrome early in her career, she has been working on the disorder alongside other research, despite the lack of enthusiasm from her colleagues, fellow researchers and funding agencies. The main reason is that very few individuals and even fewer families are available for investigation. In the 1990s, she collaborated withUta Francke fromStanford University to identify the gene responsible for Rett syndrome. In 1992, she narrowed down the target to a section of theX chromosome.[25] In 1999, apostdoctoral researcher in Zoghbi's lab identifiedMECP2 as the causative gene.[26] The MECP2protein bindsmethylatedcytosine (5-methylcytosine) inCpG sites, and is indispensable for almost allbrain cells.[12] In the paper, she and her team demonstrated that Rett syndrome was anX-linked dominant disorder, meaning that when 1 of the 2 copies of theMECP2 gene is abnormal, Rett syndrome will result.[11]
Zoghbi's team keeps studying MECP2, and discovered in 2004 that overexpressing the protein in mouse led to anautism-like neurological disorder.[27] In 2009, she found mice deficient of the Mecp2 gene (the mouse homolog of human MECP2) had lower levels ofnorepinephrine,dopamine andserotonin,[28] consistent with her clinical observations of patients of Rett syndrome in 1985. Recently, Zoghbi confirmed that the MECP2 protein also bound 5-methylcytosine not in CpG sites,[29] and that restoring the level of MECP2 protein in a subset ofneurons was sufficient to rescue some symptoms of Rett syndrome.[30]
After linking the gene Ataxin-1 to SCA1, Zoghbi's lab was approached by Dr. Jaehong Suh of theMassachusetts General Hospital's MassGeneral Institute for Neurodegenerative Disease to investigate the connection between ataxin-1 gene andAlzheimer's disease.[31] The subsequent study found that loss of ataxin-1 elevates BACE1 expression and Aβ pathology in mouse models, rendering it a potential contributor to risk and pathogenesis of Alzheimer's disease.[32]
^Orr, Harry T.; Chung, Ming-yi; Banfi, Sandro; Kwiatkowski Jr., Thomas J.; Servadio, Antonio; Beaudet, Arthur L.; McCall, Alanna E.; Duvick, Lisa A.; Ranum, Laura P. W.; Zoghbi, Huda Y. (1 July 1993). "Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1".Nature Genetics.4 (3):221–226.doi:10.1038/ng0793-221.PMID8358429.S2CID8877695.
^Cummings, Christopher J.; Mancini, Michael A.; Antalffy, Barbara; DeFranco, Donald B.; Orr, Harry T.; Zoghbi, Huda Y. (1 June 1998). "Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1".Nature Genetics.19 (2):148–154.doi:10.1038/502.PMID9620770.S2CID30029147.
^Amir, Ruthie E.; Van den Veyver, Ignatia B.; Wan, Mimi; Tran, Charles Q.; Francke, Uta; Zoghbi, Huda Y. (1 October 1999). "Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2".Nature Genetics.23 (2):185–188.doi:10.1038/13810.PMID10508514.S2CID3350350.
^Collins, Ann L.; Levenson, Jonathan M.; Vilaythong, Alexander P.; Richman, Ronald; Armstrong, Dawna L.; Noebels, Jeffrey L.; Sweatt, J. David; Zoghbi, Huda Y. (6 September 2004). "Mild overexpression of MeCP2 causes a progressive neurological disorder in mice".Human Molecular Genetics.13 (21):2679–2689.doi:10.1093/hmg/ddh282.PMID15351775.
^ab"Huda Yahya Zoghbi". Virtually Integrated Institutions for Clinical and Translational Research.Archived from the original on 21 October 2020. Retrieved14 December 2018.
