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Maternal mosaicism underlies the inheritance of a rare germline AKT3 variant which is responsible for megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in two Roma half-siblings

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EXPERIMENTAL AND MOLECULAR PATHOLOGY 2020年 115卷 104471-104471页

作者： Szalai, Renata Melegh, Bela, I Till, Agnes Ripszam, Reka Csabi, Gyorgyi Acharya, Anushree schrauwen, isabelle Leal, Suzanne M. Komoly, Samuel Kosztolanyi, Gyorgy Hadzsiev, Kinga Univ Pecs Med Sch Dept Med Genet Pecs Hungary Univ Pecs Szentagothai Res Ctr Pecs Hungary Univ Pecs Med Sch Dept Pediat Pecs Hungary Baylor Coll Med Ctr Stat Genet Dept Mol & Human Genet Houston TX 77030 USA Columbia Univ Ctr Stat Genet Sergievsky CtrMed Ctr Taub Inst Alzheimers Dis & Aging BrainDept Neuro New York NY USA Univ Pecs Med Sch Dept Neurol Pecs Hungary

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a developmental brain disorder characterized by an enlarged brain size with bilateral perisylvian polymicrogyria and a variable degree of ventriculomegaly. MPPH syndrome is associated with oromotor dysfunction, epilepsy, intellectual disability and postaxial hexadactyly. The molecular diagnosis of this disorder is established by the identification of a pathogenic variant in either AKT3, CCND2 or PIK3R2. Previously reported AKT3 variants are associated with various brain abnormalities and may lead to megalencephaly. MPPH syndrome is usually due to germline pathogenic AKT3 variants. Somatic mosaic pathogenic variants associated with hemimegalencephaly, which is similar to MPPH, have also been observed. A Hungarian Roma family with two half-siblings, which present with intellectual disability, dysmorphic features, epilepsy, brain malformations, and megalencephaly was studied. Whole exome sequencing (WES) analysis was performed. WES analysis revealed a heterozygous c.1393C > T p. (Arg465Trp) pathogenic missense AKT3 variant in both affected half-siblings. The variant was verified via Sanger sequencing and was not present in the DNA sample from the healthy mother, which was derived from peripheral blood, suggesting maternal germline mosaicism. In conclusion, this is the first report in which maternal germline mosaicism of a rare pathogenic AKT3 variant leads to autosomal dominantly inherited MPPH syndrome.

关键词： Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome AKT3 Whole exome sequencing Megalencephaly

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Correction: Further evidence of involvement of TMEM132E in autosomal recessive nonsyndromic hearing impairment

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Journal of human genetics 2022年第3期67卷 181页

作者： Khurram Liaqat Shabir Hussain Muhammad Bilal Abdul Nasir Anushree Acharya Raja Hussain Ali Shoaib Nawaz Muhammad Umair isabelle schrauwen Wasim Ahmad Suzanne M Leal Department of Biotechnology Faculty of Biological Sciences Quaid-i-Azam University Islamabad Pakistan. Center of Statistical Genetics Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA. Department of Biochemistry Faculty of Biological Sciences Quaid-i-Azam University Islamabad Pakistan. Department of Molecular Science and Technology Ajou University Suwon South Korea. Center for Statistical Genetics Gertrude H. Sergievsky Center Taub Institute for Alzheimer's Disease and the Aging Brain Department of Neurology Columbia University Medical Center New York NY USA. Division of Hematology/Oncology Boston Children's Hospital Boston MA USA. Medical Genomics Research Department King Abdullah International Medical Research Center (KAIMRC) King Saud bin Abdulaziz University for Health Science Ministry of National Guard-Health Affairs (MNGHA) Riyadh Saudi Arabia. Center of Statistical Genetics Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA. sml3@cumc.columbia.edu. Center for Statistical Genetics Gertrude H. Sergievsky Center Taub Institute for Alzheimer's Disease and the Aging Brain Department of Neurology Columbia University Medical Center New York NY USA. sml3@cumc.columbia.edu.

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Hearing impairment locus heterogeneity and identification of PLS1 as a new autosomal dominant gene in Hungarian Roma

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EUROPEAN JOURNAL OF HUMAN GENETICS 2019年第6期27卷 869-878页

作者： schrauwen, isabelle Melegh, Bela I. Chakchouk, Imen Acharya, Anushree Nasir, Abdul Poston, Alexis Cornejo-Sanchez, Diana M. Szabo, Zsolt Karosi, Tamas Bene, Judit Melegh, Bela Leal, Suzanne M. Baylor Coll Med Dept Mol & Human Genet Ctr Stat Genet Houston TX 77030 USA Univ Pecs Med Sch Dept Med Genet Pecs Hungary Szentagothai Res Ctr Pecs Hungary Ajou Univ Dept Mol Sci & Technol SPEL Suwon 443749 South Korea Univ Antioquia Medellin Fac Med Grp Mapeo Genet Antioquia 050010470 Colombia BAZ Cty Cent Hosp Dept Otolaryngol & Head & Neck Surg Miskolc Hungary Univ Teaching Hosp Miskolc Hungary

Roma are a socially and culturally distinct isolated population with genetically divergent subisolates, residing mainly across Central, Southern, and Eastern Europe. We evaluated the genetic etiology of hearing impairment (HI) in 15 Hungarian Roma families through exome sequencing. A family with autosomal dominant non-syndromic HI segregating a rare variant in the Calponin-homology 2 domain of PLS1, or Plastin 1 [p.(Leu363Phe)] was identified. Young adult Pls1 knockout mice have progressive HI and show morphological defects to their inner hair cells. There is evidence that PLS1 is important in the preservation of adult stereocilia and normal hearing. Four families segregated the European ancestral variant c.35delG [p.(Gly12fs)] in GJB2, and one family was homozygous for p.(Trp24*), an Indian subcontinent ancestral variant which is common amongst Roma from Slovakia, Czech Republic, and Spain. We also observed variants in known HI genes USH1G, USH2A, MYH9, MYO7A, and a splice site variant in MANBA (c.2158-2A>G) in a family with HI, intellectual disability, behavioral problems, and respiratory inflammation, which was previously reported in a Czech Roma family with similar features. Lastly, using multidimensional scaling and ADMIXTURE analyses, we delineate the degree of Asian/European admixture in the HI families understudy, and show that Roma individuals carrying the GJB2 p.(Trp24*) and MANBA c.2158-2A>G variants have a more pronounced South Asian background, whereas the other hearing-impaired Roma display an ancestral background similar to Europeans. We demonstrate a diverse genetic HI etiology in the Hungarian Roma and identify a new gene PLS1, for autosomal dominant human non-syndromic HI.

关键词： Clinical genetics Genetics Next-generation sequencing

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Heterozygosity mapping for human dominant trait variants

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HUMAN MUTATION 2019年第7期40卷 996-1004页

作者： Imai-Okazaki, Atsuko Li, Yi Horpaopan, Sukanya Riazalhosseini, Yasser Garshasbi, Masoud Mosse, Yael P. Zhang, Di schrauwen, isabelle Sharma, Aarushi Fann, Cathy S. J. Leal, Suzanne M. Lathrop, Mark Ott, Jurg Juntendo Univ Grad Sch Med Intractable Dis Res Ctr Diagnost & Therapeut Intractable Dis Tokyo Japan Natl Ctr Global Hlth & Med Med Genom Ctr Div Genom Med Res Tokyo Japan Rockefeller Univ Lab Stat Genet 1230 York Ave New York NY 10021 USA Shanxi Univ Finance & Econ Sch Stat Taiyuan Shanxi Peoples R China Naresuan Univ Dept Anat Fac Med Sci Phitsanulok Thailand McGill Univ Montreal PQ Canada Genome Quebec Innovat Ctr Montreal PQ Canada Tarbiat Modares Univ Dept Med Genet Fac Med Sci Tehran Iran Univ Penn Childrens Hosp Philadelphia Perelman Sch Med Dept PediatDiv Oncol Philadelphia PA 19104 USA Univ Penn Childrens Hosp Philadelphia Perelman Sch Med Dept PediatCtr Childhood Canc Res Philadelphia PA 19104 USA Baylor Coll Med Ctr Stat Genet Houston TX 77030 USA Amity Univ Inst Biotechnol Gwalior Madhya Pradesh India Acad Sinica Inst Biomed Sci Taipei Taiwan

Homozygosity mapping is a well-known technique to identify runs of homozygous variants that are likely to harbor genes responsible for autosomal recessive disease, but a comparable method for autosomal dominant traits has been lacking. We developed an approach to map dominant disease genes based on heterozygosity frequencies of sequence variants in the immediate vicinity of a dominant trait. We demonstrate through theoretical analysis that DNA variants surrounding an inherited dominant disease variant tend to have increased heterozygosity compared with variants elsewhere in the genome. We confirm existence of this phenomenon in sequence data with known dominant pathogenic variants obtained on family members and in unrelated population controls. A computer-based approach to estimating empirical significance levels associated with our test statistics shows genome-wide p-values smaller than 0.05 for many but not all of the individuals carrying a pathogenic variant.

关键词： ALSPAC computer simulation gene mapping genetic association analysis sequence variants

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Exome sequencing of families from Ghana reveals known and candidate hearing impairment genes

COMMUNICATIONS BIOLOGY

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COMMUNICATIONS BIOLOGY 2022年第1期5卷 369页

作者： Wonkam, Ambroise Adadey, Samuel Mawuli schrauwen, isabelle Aboagye, Elvis Twumasi Wonkam-Tingang, Edmond Esoh, Kevin Popel, Kalinka Manyisa, Noluthando Jonas, Mario deKock, Carmen Nembaware, Victoria Sanchez, Diana M. Cornejo Bharadwaj, Thashi Nasir, Abdul Everard, Jenna L. Kadlubowska, Magda K. Nouel-Saied, Liz M. Acharya, Anushree Quaye, Osbourne Amedofu, Geoffrey K. Awandare, Gordon A. Leal, Suzanne M. Univ Cape Town Fac Hlth Sci Div Human Genet ZA-7925 Cape Town South Africa Johns Hopkins Univ McKusick Nathans Inst Sch Med Baltimore MD 21205 USA Johns Hopkins Univ Dept Genet Med Sch Med Baltimore MD 21205 USA Univ Ghana West African Ctr Cell Biol Infect Pathogens WACCB LG 54 Accra Ghana Columbia Univ Med Ctr Ctr Stat Genet Gertrude H Sergievsky Ctr New York NY 10032 USA Columbia Univ Med Ctr Dept Neurol New York NY 10032 USA Ajou Univ Dept Mol Sci & Technol Suwon South Korea Kwame Nkrumah Univ Sci & Technol Sch Med Sci Dept Eye Ear Nose & Throat Kumasi Ghana Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Med Ctr New York NY 10032 USA

Whole-exome sequencing for 51 families in Ghana reveals 7 candidate genes associated with hearing impairment, 6 of which have previously been demonstrated to be expressed in the mouse inner ear. We investigated hearing impairment (HI) in 51 families from Ghana with at least two affected members that were negative for GJB2 pathogenic variants. DNA samples from 184 family members underwent whole-exome sequencing (WES). Variants were found in 14 known non-syndromic HI (NSHI) genes [26/51 (51.0%) families], five genes that can underlie either syndromic HI or NSHI [13/51 (25.5%)], and one syndromic HI gene [1/51 (2.0%)]. Variants in CDH23 and MYO15A contributed the most to HI [31.4% (16/51 families)]. For DSPP, an autosomal recessive mode of inheritance was detected. Post-lingual expression was observed for a family segregating a MARVELD2 variant. To our knowledge, seven novel candidate HI genes were identified (13.7%), with six associated with NSHI (INPP4B, CCDC141, MYO19, DNAH11, POTEI, and SOX9);and one (PAX8) with Waardenburg syndrome. MYO19 and DNAH11 were replicated in unrelated Ghanaian probands. Six of the novel genes were expressed in mouse inner ear. It is known that Pax8(-/-) mice do not respond to sound, and depletion of Sox9 resulted in defective vestibular structures and abnormal utricle development. Most variants (48/60;80.0%) have not previously been associated with HI. Identifying seven candidate genes in this study emphasizes the potential of novel HI genes discovery in Africa.

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Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia

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AMERICAN JOURNAL OF HUMAN GENETICS 2021年第12期108卷 2368-2384页

作者： Yap, Zheng Yie Efthymiou, Stephanie Seiffert, Simone Parra, Karen Vargas Lee, Sukyeong Nasca, Alessia Maroofian, Reza schrauwen, isabelle Pendziwiat, Manuela Jung, Sunhee Bhoj, Elizabeth Striano, Pasquale Mankad, Kshitij Vona, Barbara Cuddapah, Sanmati Wagner, Anja Alvi, Javeria Raza Davoudi-Dehaghani, Elham Fallah, Mohammad-Sadegh Gannavarapu, Srinitya Lamperti, Costanza Legati, Andrea Murtaza, Bibi Nazia Nadeem, Muhammad Shahid Rehman, Mujaddad Ur Saeidi, Kolsoum Salpietro, Vincenzo von Spiczak, Sarah Sandoval, Abigail Zeinali, Sirous Zeviani, Massimo Reich, Adi Jang, Cholsoon Helbig, Ingo Barakat, Tahsin Stefan Ghezzi, Daniele Leal, Suzanne M. Weber, Yvonne Houlden, Henry Yoon, Wan Hee Oklahoma Med Res Fdn Aging & Metab Res Program Oklahoma City OK 73104 USA UCL Queen Sq Inst Neurol Dept Neuromuscular Disorders London WC1N 3BG England Univ Tubingen Dept Neurol & Epileptol Hertie Inst Clin Brain Res D-72076 Tubingen Germany Baylor Coll Med Verna & Marrs McLean Dept Biochem & Mol Biol Houston TX 77030 USA Fdn IRCCS Ist Neurol Carlo Besta Unit Med Genet & Neurogenet Via Temolo 4 I-20126 Milan Italy Columbia Univ Med Ctr Gertrude H Sergievsky Ctr Ctr Stat Genet New York NY 10032 USA Columbia Univ Med Ctr Dept Neurol New York NY 10032 USA Christian Albrechts Univ Kiel Inst Clin Mol Biol D-24105 Kiel Germany Univ Calif Irvine Dept Biol Chem Irvine CA 92717 USA Childrens Hosp Philadelphia Div Human Genet Philadelphia PA 19104 USA Univ Penn Dept Pediat Perelman Sch Med Philadelphia PA 19104 USA Univ Genoa Dept Neurosci Rehabil Ophthalmol Genet Maternal & I-16124 Genoa Italy IRCCS Pediat Neurol & Muscular Dis Unit Ist Giannina Gaslini I-16123 Genoa Italy Great Ormond St Hosp Sick Children Neuroradiol Unit London WC1N3JH England Eberhard Karls Univ Tubingen Dept Otolaryngol Head & Neck Surg Tubingen Hearing Res Ctr D-72076 Tubingen Germany Erasmus MC Erasmus MC Canc Inst Dept Clin Genet NL-3000 Rotterdam Netherlands Children Hosp Lahore Inst Child Hlth Dept Pediat Neurol Lahore 54600 Pakistan Pasteur Inst Iran Dept Mol Med Biotechnol Res Ctr Tehran *** Iran Kawsar Human Genet Res Ctr Dept Med Genet Tehran *** Iran Western Univ Dept Pathol & Lab Med London ON N6A 5C1 Canada Abbottabad Univ Sci & Technol Dept Zool Abbottabad 22500 Pakistan King Abdulaziz Univ Dept Biochem Jeddah 21589 Saudi Arabia Abbottabad Univ Sci & Technol Dept Microbiol Abbottabad 22500 Pakistan Kerman Univ Med Sci Inst Neuropharmacol Neurosci Res Ctr Kerman *** Iran DRK Northern German Epilepsy Ctr Children & Adole D-24223 Schwentinental Raisdorf Germany Univ Padua Dept Neurosci Via Giustiniani 2 I-35128 Padua Italy GeneDx Gaithersburg MD 208

The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous mis sense variants (***852Ala, ***244Trp, and ***299Gly), three compound heterozygous single-nucleotide variants (***673Gln/***488Val, ***734Ser/***327Val, and ***220Cys/***491Val), one homozygous frame shift variant (***553Leufs*16), and one homozygous stop-gain variant (***440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that ***673Gln, ***734Ser, and ***299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas ***852Ala, ***327Val, ***220Cys, ***491Val, and ***244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T> C [***488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in h

关键词： OGDHL mitochondria α-ketoglutarate bi-allelic developmental and epileptic encephalopathy DEE exome sequencing Drosophila CRISPR-Cas9 gene editing neurodevelopmental disease

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Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome

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HUMAN MUTATION 2019年第2期40卷 162-176页

作者： Faridi, Rabia Tona, Risa Brofferio, Alessandra Hoa, Michael Olszewski, Rafal schrauwen, isabelle Assir, Muhammad Z. K. Bandesha, Akhtar A. Khan, Asma A. Rehman, Atteeq U. Brewer, Carmen Ahmed, Wasim Leal, Suzanne M. Riazuddin, Sheikh Boyden, Steven E. Friedman, Thomas B. Natl Inst Deafness & Other Commun Disorders Lab Mol Genet NIH Bethesda MD USA Univ Punjab Natl Ctr Excellence Mol Biol Lahore Pakistan NHLBI Cardiol Branch NIH Clin Ctr Bldg 10 Bethesda MD 20892 USA Natl Inst Deafness & Other Commun Disorders Auditory Dev & Restorat Program NIH Bethesda MD USA Baylor Coll Med Dept Mol & Human Genet Ctr Stat Genet Houston TX 77030 USA Jinnah Hosp Complex Allama Iqbal Med Res Ctr Lahore Pakistan Pakistan Inst Med Sci Cardiol Dept Islamabad Pakistan Natl Inst Deafness & Other Commun Disorders NIDCD Audiol Unit NIH Bethesda MD USA Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad Pakistan Natl Inst Deafness & Other Commun Disorders Sect Genet Commun Disorders NIH Bethesda MD USA New York Genome Ctr Clin Lab New York NY USA Univ Utah Dept Human Genet USTAR Ctr Genet Discovery Salt Lake City UT USA

KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel-complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange-Nielson syndrome (JLNS1 and JLNS2), a cardio-auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Some normal-hearing carriers of heterozygous missense variants of KCNE1 and KCNQ1 have prolonged QT intervals, a dominantly inherited phenotype designated Romano-Ward syndrome (RWS), which is also associated with arrhythmias and elevated risk of sudden death. Coassembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism. This paper reviews variants of KCNE1 and their associated phenotypes, including biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50G>A (***17*), c.51G>A (***17*), and c.138C>A (***46*). Some individuals carrying missense variants of KCNE1 have RWS. However, heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype-phenotype spectrum for KCNE1 variants.

关键词： deafness Jervell and Lange-Nielson syndrome KCNE1 KCNQ1 prolonged-QT Romano-Ward syndrome

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Compound heterozygous mutations in SNAP29 is associated with Pelizaeus-Merzbacher-like disorder (PMLD)

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HUMAN GENETICS 2019年第11-12期138卷 1409-1417页

作者： Llaci, Lorida Ramsey, Keri Belnap, Newell Claasen, Ana M. Balak, Chris D. Szelinger, Szabolcs Jepsen, Wayne M. Siniard, Ashley L. Richholt, Ryan Izat, Tyler Naymik, Marcus De Both, Matt Piras, Ignazio S. Craig, David W. Huentelman, Matthew J. Narayanan, Vinodh schrauwen, isabelle Rangasamy, Sampathkumar Translat Genom Res Inst Ctr Rare Childhood Disorders Phoenix AZ 85004 USA Translat Genom Res Inst Neurogen Div Phoenix AZ 85004 USA Univ Southern Calif Dept Translat Genom Los Angeles CA USA Columbia Univ Dept Neurol Ctr Stat Genet Gertrude H Sergievsky CtrMed Ctr New York NY 10027 USA

Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating leukodystrophy, which is clinically and radiologically similar to X-linked Pelizaeus-Merzbacher disease (PMD). PMLD is characterized by early-onset nystagmus, delayed development (motor delay, speech delay and dysarthria), dystonia, hypotonia typically evolving into spasticity, ataxia, seizures, optic atrophy, and diffuse leukodystrophy on magnetic resonance imaging (MRI). We identified a 12-year-old Caucasian/Hispanic male with the classical clinical characteristics of PMLD with lack of myelination of the subcortical white matter, and absence of the splenium of corpus callosum. Exome sequencing in the trio revealed novel compound heterozygous pathogenic mutations in SNAP29 (***119AlafsX15, c.354DupG and p.0?, c.2T > C). Quantitative analysis of the patient's blood cells through RNA sequencing identified a significant decrease in SNAP29 mRNA expression, while western blot analysis on fibroblast cells revealed a lack of protein expression compared to parental and control cells. Mutations in SNAP29 have previously been associated with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome. Typical skin features described in CEDNIK syndrome, such as generalized ichthyosis and keratoderma, were absent in our patient. Moreover, the early onset nystagmus and leukodystrophy were consistent with a PMLD diagnosis. These findings suggest that loss of SNAP29 function, which was previously associated with CEDNIK syndrome, is also associated with PMLD. Overall, our study expands the genetic spectrum of PMLD.

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A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment

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HUMAN GENETICS 2018年第6-7期137卷 471-478页

作者： schrauwen, isabelle Chakchouk, Imen Liaqat, Khurram Jan, Abid Nasir, Abdul Hussain, Shabir Nickerson, Deborah A. Bamshad, Michael J. Ullah, Asmat Ahmad, Wasim Leal, Suzanne M. Baylor Coll Med Ctr Stat Genet Dept Mol & Human Genet One Baylor Plaza 700D Houston TX 77030 USA Quaid I Azam Univ Fac Biol Sci Dept Biotechnol Islamabad Pakistan Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad Pakistan Ajou Univ Dept Mol Sci & Technol SPEL Suwon 443749 South Korea Univ Washington Dept Genome Sci Seattle WA 98195 USA Univ Washington Dept Pediat Seattle WA 98195 USA

Hereditary hearing impairment is a common sensory disorder that is genetically and phenotypically heterogeneous. In this study, we used a homozygosity mapping and exome sequencing strategy to study a consanguineous Pakistani family with autosomal recessive severe-to-profound hearing impairment. This led to the identification of a missense variant (***369Thr) in the LMX1A gene affecting a conserved residue in the C-terminus of the protein, which was predicted damaging by an in silico bioinformatics analysis. The ***369Thr variant disrupts several C-terminal and homeodomain residue interactions, including an interaction with homeodomain residue ***241 that was previously found to be involved in autosomal dominant progressive HI. LIM-homeodomain factor Lmx1a is expressed in the inner ear through development, shows a progressive restriction to non-sensory epithelia, and is important in the separation of the sensory and non-sensory domains in the inner ear. Homozygous Lmx1a mutant mice (Dreher) are deaf with dysmorphic ears with an abnormal morphogenesis and fused and misshapen sensory organs;however, computed tomography performed on a hearing-impaired family member did not reveal any cochleovestibular malformations. Our results suggest that LMX1A is involved in both human autosomal recessive and dominant sensorineural hearing impairment.

关键词： LMX1A Autosomal recessive hearing impairment Deafness Exome sequencing

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FAM92A Underlies Nonsyndromic Postaxial Polydactyly in Humans and an Abnormal Limb and Digit Skeletal Phenotype in Mice

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JOURNAL OF BONE AND MINERAL RESEARCH 2019年第2期34卷 375-386页

作者： schrauwen, isabelle Giese, Arnaud P. J. Aziz, Abdul Lafont, David Tino Chakchouk, Imen Santos-Cortez, Regie Lyn P. Lee, Kwanghyuk Acharya, Anushree Khan, Falak Sher Ullah, Asmat Nickerson, Deborah A. Bamshad, Michael J. Ali, Ghazanfar Riazuddin, Saima Ansar, Muhammad Ahmad, Wasim Ahmed, Zubair M. Leal, Suzanne M. Baylor Coll Med Ctr Stat Genet Dept Mol & Human Genet 1 Baylor Plaza 700D Houston TX 77030 USA Univ Maryland Sch Med Otorhinolaryngol Head & Neck Surg Baltimore MD 21201 USA Quaid I Azam Univ Dept Biochem Fac Biol Sci Islamabad Pakistan Khushal Khan Khattak Univ Dept Comp Sci & Bioinformat Karak Pakistan Sanger Inst Wellcome Trust Genome Campus Hinxton England Univ Washington Dept Genome Sci Seattle WA 98195 USA Univ Washington Dept Pediat Seattle WA 98195 USA Univ Azad Jammu & Kashmir Dept Biotechnol Muzaffarabad Pakistan

Polydactyly is a common congenital anomaly of the hand and foot. Postaxial polydactyly (PAP) is characterized by one or more posterior or postaxial digits. In a Pakistani family with autosomal recessive nonsyndromic postaxial polydactyly type A (PAPA), we performed genomewide genotyping, linkage analysis, and exome and Sanger sequencing. Exome sequencing revealed a homozygous nonsense variant (c.478C>T, p.[Arg160*]) in the FAM92A gene within the mapped region on 8q21.13-q24.12 that segregated with the PAPA phenotype. We found that FAM92A is expressed in the developing mouse limb and E11.5 limb bud including the progress zone and the apical ectodermal ridge, where it strongly localizes at the cilia level, suggesting an important role in limb patterning. The identified variant leads to a loss of the FAM92A/Chibby1 complex that is crucial for ciliogenesis and impairs the recruitment and the colocalization of FAM92A with Chibby1 at the base of the cilia. In addition, we show that Fam92a(-/-) homozygous mice also exhibit an abnormal digit morphology, including metatarsal osteomas and polysyndactyly, in addition to distinct abnormalities on the deltoid tuberosity of their humeri. In conclusion, we present a new nonsyndromic PAPA ciliopathy due to a loss-of-function variant in FAM92A. (c) 2018 American Society for Bone and Mineral Research.

关键词： CILIOPATHY POSTAXIAL POLYDACTYLY FAM92A CHIBBY1 PAPA

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