Robert Morell - Academia.edu (original) (raw)
Papers by Robert Morell
Journal of Medical Genetics, May 4, 2015
Frontiers in Cellular Neuroscience, Nov 23, 2018
American Journal of Human Genetics, Sep 1, 2000
Clinical Genetics, Nov 16, 2016
Human Genetics
Enlargement of the endolymphatic sac, duct, and vestibular aqueduct (EVA) is the most common inne... more Enlargement of the endolymphatic sac, duct, and vestibular aqueduct (EVA) is the most common inner ear malformation identified in patients with sensorineural hearing loss. EVA is associated with pathogenic variants in SLC26A4. However, in European–Caucasian populations, about 50% of patients with EVA carry no pathogenic alleles of SLC26A4. We tested for the presence of variants in CHD7, a gene known to be associated with CHARGE syndrome, Kallmann syndrome, and hypogonadotropic hypogonadism, in a cohort of 34 families with EVA subjects without pathogenic alleles of SLC26A4. In two families, NM_017780.4: c.3553A > G [p.(Met1185Val)] and c.5390G > C [p.(Gly1797Ala)] were detected as monoallelic CHD7 variants in patients with EVA. At least one subject from each family had additional signs or potential signs of CHARGE syndrome but did not meet diagnostic criteria for CHARGE. In silico modeling of these two missense substitutions predicted detrimental effects upon CHD7 protein struc...
BackgroundPrevious studies identified a strong linkage signal for non-syndromic persistent develo... more BackgroundPrevious studies identified a strong linkage signal for non-syndromic persistent developmental stuttering on chromosome 3q13.2-3q13.33 in a large consanguineous family. To identify the causative genetic variant at this locus, including we performed further analysis, including whole exome, whole genome, and targeting Sanger sequencing.ResultsWe identified a homozygous rare c.2155G>A variant inZBTB20in individuals who stutter. This mutation encodes Isoleucine in place of a highly conserved Valine at amino acid position 719 in ZBTB20 that co-segregates (LOD = 4.23) with stuttering under a model of recessive inheritance with reduced penetrance in this family. Coding variants in this gene were significantly more frequent in a multiethnic cohort of unrelated individuals who stutter than in individuals in large population databases comprised of our normal control subjects and gnomAD database subjects matched for ethnicity.ZBTB20encodes a zinc-finger transcription factor, and l...
Frontiers in Molecular Neuroscience, 2021
American Journal of Human Genetics, 1994
Genotypes for 53 simple tandem repeat (STR) markers distributed at greater than 39 cM intervals t... more Genotypes for 53 simple tandem repeat (STR) markers distributed at greater than 39 cM intervals throughout the genome were determined for 46 individuals from the village of Bengkala, Bali. This village dates to at least the thirteenth century, has approximately 2,200 individuals and has an oral and written tradition suggesting genetic bottlenecks. The allele frequency distributions in Bengkala were compared with distributions obtained by typing individuals in the CEPH data base using a Kolmogorov-Smirnov two sample test. Twenty-eight of the 53 markers showed differences (p<0.05) in distribution between the two populations. Allele frequencies of tetranucleotide STRs were much more similar between the two populations than were those of dinucleotide STRs (p < 0.0043). This may be due to the higher mutation rate of tetranucleotide STRs, combining with selection on repeat lengths, to produce a {open_quotes}stable{close_quotes} allele distribution. Population heterogeneity in Bengka...
El Sindrome de Waardenburg (WS) es un desorden autosomico dominante caracterizado por sordera neu... more El Sindrome de Waardenburg (WS) es un desorden autosomico dominante caracterizado por sordera neurosensorial y anormalidades pigmentarias en la piel y faneras. Es clinica y geneticamente heterogeneo y ha sido dividido en 4 subtipos. Segun la presencia o ausencia de distopia cantorum (desplazamiento lateral del canto interno de los ojos), se subdividen en WS 1 (gen PAX 3) y WS 2 (gen MITF), respectivamente.
Clinical Genetics, 2020
Usher syndrome has been historically categorized into one of three classical types based on the p... more Usher syndrome has been historically categorized into one of three classical types based on the patient phenotype. However, the vestibular phenotype does not infallibly predict which Usher genes are mutated. Conversely, the Usher syndrome genotype is not sufficient to reliably predict vestibular function. Here we present a characterization of the vestibular phenotype of 90 patients with clinical presentation of Usher syndrome (59 females), aged 10.9 to 75.5 years, with genetic variants in eight Usher syndromic genes and expand the description of atypical Usher syndrome. We identified unexpected horizontal semicircular canal reactivity in response to caloric and rotational stimuli in 12.5% (3 of 24) and 41.7% (10 of 24), respectively, of our USH1 cohort. These findings are not consistent with the classical phenotypic definition of vestibular areflexia in USH1. Similarly, 17% (6 of 35) of our cohort with USH2A mutations had saccular dysfunction as evidenced by absent cervical vestibul...
American journal of human genetics, 1991
Waardenburg syndrome type I (WS1; MIM 19350) is caused by a pleiotropic, autosomal dominant mutat... more Waardenburg syndrome type I (WS1; MIM 19350) is caused by a pleiotropic, autosomal dominant mutation with variable penetrance and expressivity. Of individuals with this mutation, 20%-25% are hearing impaired. A multilocus linkage analysis of RFLP data from a single WS1 family with 11 affected individuals indicates that the WS1 mutation in this family is linked to the following four marker loci located on the long arm of chromosome 2: ALPP (alkaline phosphatase, placental), FN1 (fibronectin 1), D2S3 (a unique-copy DNA segment), and COL6A3 (collagen VI, alpha 3). For the RFLP marker loci, a multilocus linkage analysis using MLINK produced a peak lod (Z) of 3.23 for the following linkage relationships and recombination fractions (theta i): (ALPP----.000----FN1)----.122----D2S3----.267----CO L6A3. A similar analysis produced a Z of 6.67 for the following linkage relationships and theta i values among the markers and WS1: (FN1----.000----WS1----.000----ALPP)----.123----D2S 3----.246----C...
American Journal of Human Genetics, Mar 1, 2010
Frontiers in Molecular Neuroscience, 2021
The endocochlear potential (EP) generated by the stria vascularis (SV) is necessary for hair cell... more The endocochlear potential (EP) generated by the stria vascularis (SV) is necessary for hair cell mechanotransduction in the mammalian cochlea. We sought to create a model of EP dysfunction for the purposes of transcriptional analysis and treatment testing. By administering a single dose of cisplatin, a commonly prescribed cancer treatment drug with ototoxic side effects, to the adult mouse, we acutely disrupt EP generation. By combining these data with single cell RNA-sequencing findings, we identify transcriptional changes induced by cisplatin exposure, and by extension transcriptional changes accompanying EP reduction, in the major cell types of the SV. We use these data to identify gene regulatory networks unique to cisplatin treated SV, as well as the differentially expressed and druggable gene targets within those networks. Our results reconstruct transcriptional responses that occur in gene expression on the cellular level while identifying possible targets for interventions ...
Neurogenetics, Feb 16, 2016
TMC1 encodes a protein required for the normal function of mechanically-activated channels that e... more TMC1 encodes a protein required for the normal function of mechanically-activated channels that enable sensory transduction in auditory and vestibular hair cells. TMC1 protein is localized at the tips of the hair cell stereocilia, the site of conventional mechanotransduction. In many populations, loss-of-function recessive mutations of TMC1 are associated with profound deafness across all frequencies tested. In six families reported here, variable moderate-to-severe or moderate-toprofound hearing loss co-segregated with STR (short tandem repeats) markers at the TMC1 locus DFNB7/11. Massively parallel and Sanger sequencing of genomic DNA revealed each family cosegregating hearing loss with a homozygous TMC1 mutation; two reported mutations (p.R34X and p.R389Q), and three novel mutations (p.S596R, p.N199I and c.1404+1G>T). TMC1 cDNA sequence from affected subjects homozygous for the donor splice site transversion c.1404+1G>T revealed skipping of exon 16, deleting 60 amino acids from the TMC1 protein. Since the mutations in our study cause less than profound hearing loss, we speculate that there is hypofunctional TMC1 mechanotransduction channel activity and that other even less damaging variants of TMC1 may be associated with more common mild-to-severe sensorineural hearing loss.
Journal of Medical Genetics, Apr 1, 2004
Science, May 29, 1998
tion is likely to destroy actin binding of Myol5, creating a loss-of-function allele. Myol5 led t... more tion is likely to destroy actin binding of Myol5, creating a loss-of-function allele. Myol5 led to identification of the human homolog, MY015, and to the discovery of a nonsense mutation and two missense mutations in three unrelated human families with nonsyndromic, congenital deafness, DFNB3 (9). Mutations in three different unconventional myosins, Myol5 sh2 , Myo6 sv , and My o7a shl , cause deafness (13). Morphology and histology of severe loss-of-function alleles in the mouse suggest that each of these myosins has a unique function in the hair cells of the inner ear. Our results show that Myol5 is involved in the maintenance of actin organization in the hair cells of the organ of Corti. Loss of Myo7a causes disorganization of the characteristic pattern of the stereocilia early in development, whereas loss of My 06 function causes fusion of the stereocilia and loss of the inner hair cells and support cells by 6 weeks of age (14). In contrast, the inner hair cells of sh2 mutants survive longer (15) and the abnormally short stereocilia are arranged in a nearly normal pattern on the hair cell surface. These features make shaker-2 mice a good model for examining the role of a unique unconventional myosin in the auditory system and for the exploration of mechanisms for the delivery of functional proteins to surviving mutant hair cells.
npj Regenerative Medicine
The mechanisms that prevent regeneration of irradiated (IR) salivary glands remain elusive. Bulk ... more The mechanisms that prevent regeneration of irradiated (IR) salivary glands remain elusive. Bulk RNAseq of IR versus non-IR human salivary glands showed that neurotrophin signaling is highly disrupted post-radiation. Neurotrophin receptors (NTRs) were significantly upregulated in myoepithelial cells (MECs) post-IR, and single cell RNAseq revealed that MECs pericytes, and duct cells are the main sources of neurotrophin ligands. Using two ex vivo models, we show that nerve growth factor (NGF) induces expression of MEC genes during development, and upregulation of NTRs in adult MECs is associated with stress-induced plasticity and morphological abnormalities in IR human glands. As MECs are epithelial progenitors after gland damage and are required for proper acinar cell contraction and secretion, we propose that MEC-specific upregulation of NTRs post-IR disrupts MEC differentiation and potentially impedes the ability of the gland to regenerate.
Journal of Medical Genetics, May 4, 2015
Frontiers in Cellular Neuroscience, Nov 23, 2018
American Journal of Human Genetics, Sep 1, 2000
Clinical Genetics, Nov 16, 2016
Human Genetics
Enlargement of the endolymphatic sac, duct, and vestibular aqueduct (EVA) is the most common inne... more Enlargement of the endolymphatic sac, duct, and vestibular aqueduct (EVA) is the most common inner ear malformation identified in patients with sensorineural hearing loss. EVA is associated with pathogenic variants in SLC26A4. However, in European–Caucasian populations, about 50% of patients with EVA carry no pathogenic alleles of SLC26A4. We tested for the presence of variants in CHD7, a gene known to be associated with CHARGE syndrome, Kallmann syndrome, and hypogonadotropic hypogonadism, in a cohort of 34 families with EVA subjects without pathogenic alleles of SLC26A4. In two families, NM_017780.4: c.3553A > G [p.(Met1185Val)] and c.5390G > C [p.(Gly1797Ala)] were detected as monoallelic CHD7 variants in patients with EVA. At least one subject from each family had additional signs or potential signs of CHARGE syndrome but did not meet diagnostic criteria for CHARGE. In silico modeling of these two missense substitutions predicted detrimental effects upon CHD7 protein struc...
BackgroundPrevious studies identified a strong linkage signal for non-syndromic persistent develo... more BackgroundPrevious studies identified a strong linkage signal for non-syndromic persistent developmental stuttering on chromosome 3q13.2-3q13.33 in a large consanguineous family. To identify the causative genetic variant at this locus, including we performed further analysis, including whole exome, whole genome, and targeting Sanger sequencing.ResultsWe identified a homozygous rare c.2155G>A variant inZBTB20in individuals who stutter. This mutation encodes Isoleucine in place of a highly conserved Valine at amino acid position 719 in ZBTB20 that co-segregates (LOD = 4.23) with stuttering under a model of recessive inheritance with reduced penetrance in this family. Coding variants in this gene were significantly more frequent in a multiethnic cohort of unrelated individuals who stutter than in individuals in large population databases comprised of our normal control subjects and gnomAD database subjects matched for ethnicity.ZBTB20encodes a zinc-finger transcription factor, and l...
Frontiers in Molecular Neuroscience, 2021
American Journal of Human Genetics, 1994
Genotypes for 53 simple tandem repeat (STR) markers distributed at greater than 39 cM intervals t... more Genotypes for 53 simple tandem repeat (STR) markers distributed at greater than 39 cM intervals throughout the genome were determined for 46 individuals from the village of Bengkala, Bali. This village dates to at least the thirteenth century, has approximately 2,200 individuals and has an oral and written tradition suggesting genetic bottlenecks. The allele frequency distributions in Bengkala were compared with distributions obtained by typing individuals in the CEPH data base using a Kolmogorov-Smirnov two sample test. Twenty-eight of the 53 markers showed differences (p<0.05) in distribution between the two populations. Allele frequencies of tetranucleotide STRs were much more similar between the two populations than were those of dinucleotide STRs (p < 0.0043). This may be due to the higher mutation rate of tetranucleotide STRs, combining with selection on repeat lengths, to produce a {open_quotes}stable{close_quotes} allele distribution. Population heterogeneity in Bengka...
El Sindrome de Waardenburg (WS) es un desorden autosomico dominante caracterizado por sordera neu... more El Sindrome de Waardenburg (WS) es un desorden autosomico dominante caracterizado por sordera neurosensorial y anormalidades pigmentarias en la piel y faneras. Es clinica y geneticamente heterogeneo y ha sido dividido en 4 subtipos. Segun la presencia o ausencia de distopia cantorum (desplazamiento lateral del canto interno de los ojos), se subdividen en WS 1 (gen PAX 3) y WS 2 (gen MITF), respectivamente.
Clinical Genetics, 2020
Usher syndrome has been historically categorized into one of three classical types based on the p... more Usher syndrome has been historically categorized into one of three classical types based on the patient phenotype. However, the vestibular phenotype does not infallibly predict which Usher genes are mutated. Conversely, the Usher syndrome genotype is not sufficient to reliably predict vestibular function. Here we present a characterization of the vestibular phenotype of 90 patients with clinical presentation of Usher syndrome (59 females), aged 10.9 to 75.5 years, with genetic variants in eight Usher syndromic genes and expand the description of atypical Usher syndrome. We identified unexpected horizontal semicircular canal reactivity in response to caloric and rotational stimuli in 12.5% (3 of 24) and 41.7% (10 of 24), respectively, of our USH1 cohort. These findings are not consistent with the classical phenotypic definition of vestibular areflexia in USH1. Similarly, 17% (6 of 35) of our cohort with USH2A mutations had saccular dysfunction as evidenced by absent cervical vestibul...
American journal of human genetics, 1991
Waardenburg syndrome type I (WS1; MIM 19350) is caused by a pleiotropic, autosomal dominant mutat... more Waardenburg syndrome type I (WS1; MIM 19350) is caused by a pleiotropic, autosomal dominant mutation with variable penetrance and expressivity. Of individuals with this mutation, 20%-25% are hearing impaired. A multilocus linkage analysis of RFLP data from a single WS1 family with 11 affected individuals indicates that the WS1 mutation in this family is linked to the following four marker loci located on the long arm of chromosome 2: ALPP (alkaline phosphatase, placental), FN1 (fibronectin 1), D2S3 (a unique-copy DNA segment), and COL6A3 (collagen VI, alpha 3). For the RFLP marker loci, a multilocus linkage analysis using MLINK produced a peak lod (Z) of 3.23 for the following linkage relationships and recombination fractions (theta i): (ALPP----.000----FN1)----.122----D2S3----.267----CO L6A3. A similar analysis produced a Z of 6.67 for the following linkage relationships and theta i values among the markers and WS1: (FN1----.000----WS1----.000----ALPP)----.123----D2S 3----.246----C...
American Journal of Human Genetics, Mar 1, 2010
Frontiers in Molecular Neuroscience, 2021
The endocochlear potential (EP) generated by the stria vascularis (SV) is necessary for hair cell... more The endocochlear potential (EP) generated by the stria vascularis (SV) is necessary for hair cell mechanotransduction in the mammalian cochlea. We sought to create a model of EP dysfunction for the purposes of transcriptional analysis and treatment testing. By administering a single dose of cisplatin, a commonly prescribed cancer treatment drug with ototoxic side effects, to the adult mouse, we acutely disrupt EP generation. By combining these data with single cell RNA-sequencing findings, we identify transcriptional changes induced by cisplatin exposure, and by extension transcriptional changes accompanying EP reduction, in the major cell types of the SV. We use these data to identify gene regulatory networks unique to cisplatin treated SV, as well as the differentially expressed and druggable gene targets within those networks. Our results reconstruct transcriptional responses that occur in gene expression on the cellular level while identifying possible targets for interventions ...
Neurogenetics, Feb 16, 2016
TMC1 encodes a protein required for the normal function of mechanically-activated channels that e... more TMC1 encodes a protein required for the normal function of mechanically-activated channels that enable sensory transduction in auditory and vestibular hair cells. TMC1 protein is localized at the tips of the hair cell stereocilia, the site of conventional mechanotransduction. In many populations, loss-of-function recessive mutations of TMC1 are associated with profound deafness across all frequencies tested. In six families reported here, variable moderate-to-severe or moderate-toprofound hearing loss co-segregated with STR (short tandem repeats) markers at the TMC1 locus DFNB7/11. Massively parallel and Sanger sequencing of genomic DNA revealed each family cosegregating hearing loss with a homozygous TMC1 mutation; two reported mutations (p.R34X and p.R389Q), and three novel mutations (p.S596R, p.N199I and c.1404+1G>T). TMC1 cDNA sequence from affected subjects homozygous for the donor splice site transversion c.1404+1G>T revealed skipping of exon 16, deleting 60 amino acids from the TMC1 protein. Since the mutations in our study cause less than profound hearing loss, we speculate that there is hypofunctional TMC1 mechanotransduction channel activity and that other even less damaging variants of TMC1 may be associated with more common mild-to-severe sensorineural hearing loss.
Journal of Medical Genetics, Apr 1, 2004
Science, May 29, 1998
tion is likely to destroy actin binding of Myol5, creating a loss-of-function allele. Myol5 led t... more tion is likely to destroy actin binding of Myol5, creating a loss-of-function allele. Myol5 led to identification of the human homolog, MY015, and to the discovery of a nonsense mutation and two missense mutations in three unrelated human families with nonsyndromic, congenital deafness, DFNB3 (9). Mutations in three different unconventional myosins, Myol5 sh2 , Myo6 sv , and My o7a shl , cause deafness (13). Morphology and histology of severe loss-of-function alleles in the mouse suggest that each of these myosins has a unique function in the hair cells of the inner ear. Our results show that Myol5 is involved in the maintenance of actin organization in the hair cells of the organ of Corti. Loss of Myo7a causes disorganization of the characteristic pattern of the stereocilia early in development, whereas loss of My 06 function causes fusion of the stereocilia and loss of the inner hair cells and support cells by 6 weeks of age (14). In contrast, the inner hair cells of sh2 mutants survive longer (15) and the abnormally short stereocilia are arranged in a nearly normal pattern on the hair cell surface. These features make shaker-2 mice a good model for examining the role of a unique unconventional myosin in the auditory system and for the exploration of mechanisms for the delivery of functional proteins to surviving mutant hair cells.
npj Regenerative Medicine
The mechanisms that prevent regeneration of irradiated (IR) salivary glands remain elusive. Bulk ... more The mechanisms that prevent regeneration of irradiated (IR) salivary glands remain elusive. Bulk RNAseq of IR versus non-IR human salivary glands showed that neurotrophin signaling is highly disrupted post-radiation. Neurotrophin receptors (NTRs) were significantly upregulated in myoepithelial cells (MECs) post-IR, and single cell RNAseq revealed that MECs pericytes, and duct cells are the main sources of neurotrophin ligands. Using two ex vivo models, we show that nerve growth factor (NGF) induces expression of MEC genes during development, and upregulation of NTRs in adult MECs is associated with stress-induced plasticity and morphological abnormalities in IR human glands. As MECs are epithelial progenitors after gland damage and are required for proper acinar cell contraction and secretion, we propose that MEC-specific upregulation of NTRs post-IR disrupts MEC differentiation and potentially impedes the ability of the gland to regenerate.