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Unraveling the molecular basis genetically heterogeneous developmental eye disorders

Basamat Almoallem Mohammed UGent (2017)
abstract
Vision is one of the most important senses of a human being. It is estimated that 285 million people worldwide suffer from visual impairment. Although the etiology of visual impairment is rather complex, genetic factors play an important role. In this respect, developmental eye disorders have a huge impact on childhood visual impairment and blindness. Here, we focus on three types of developmental eye disorders including: idiopathic infantile nystagmus (IIN), Leber congenital amaurosis (LCA), nanophthalmos and posterior microphthalmia (NNO and MOCP) caused by mutations encoding many different signaling and structural proteins in the developing eye. The pursuit of the molecular diagnosis in these conditions is challenging as they have been hampered by a tremendous clinical and genetic heterogeneity where different modes of Mendelian inheritance can be found. In the first study of this thesis the role of mutations and copy number variations (CNV) of FRMD7 and GPR143 was investigated in 49 unrelated Belgian probands with a possible diagnosis of X-linked idiopathic infantile nystagmus (XLIIN). Our comprehensive molecular workflow consisted of targeted gene screening using Sanger sequencing and next generation sequencing (NGS), followed by multiplex ligation–dependent probe amplification. This revealed a genetic defect in FRMD7 in 11 of 49 (22.4%) of the studied probands, including a deletion of 1.29 Mb containing FRMD7 in a syndromic patient with nystagmus and autism spectrum disorder. This study expanded the mutational spectrum of FRMD7 in XLIIN and generated a discovery cohort of IIN patients potentially harboring either hidden genetic variation such as deep intronic or cis-regulatory mutations within FRMD7 or mutations in other genes at known or novel loci. The second study was targeting 15 consanguineous Saudi families including 20 patients with an initial diagnosis of LCA. A combined approach of homozygosity mapping, targeted gene screening and whole exome sequencing (WES) was applied to unveil the underlying genetic cause in these families. Overall, this strategy identified the causative mutations in all but one (14/15, 93.3%) of the studied families, guiding refinement of the clinical diagnosis. Specifically, twelve unique homozygous mutations were identified in eight known LCA genes: CABP4, CEP290, CRB1, GUCY2D, MERTK, RDH12, RPGRIP1 and SPATA7. In addition, one novel mutation was found in the recently identified achromatopsia gene ATF6, leading to a clinical diagnosis of achromatopsia in retrospect. Apart from mutations in known disease genes, a homozygous pathogenic variant was found in RIMS2 (Regulating Synaptic Membrane Exocytosis 2) in two affected sibs with LCA and autism spectrum disorder. The expression of RIMS2 in the retina and several brain structures of human, mouse and zebrafish is consistent with the observed phenotype in these sibs. Moreover, RIMS2 is known to play a role in maintaining the photoreceptor ribbon synapse and has been shown previously to be associated with Asperger syndrome, an autism subtype. Interestingly, the paralog RIMS1 was previously shown to be mutated in autosomal dominant cone-rod dystrophy (CORD7) and to be implicated in autism. The identification of RIMS2 as novel candidate gene for LCA and autism link a synaptic protein with autosomal recessive IRD and autism. Finally, the third study of this doctoral project investigated the role of MFRP and PRSS56 mutations in nanophthalmos (NNO) and posterior microphthalmia (MCOP) in a cohort of 21 unrelated patients from a different ethnic origin. The genetic approach consisted of targeted gene screening and homozygosity mapping in families with a consanguineous background. This revealed the underlying genetic cause in all but two (19/21, 90.5%) of the studied families, with either homozygous or compound heterozygous distinct mutations in MFRP (10/21, 47.6%) and PRSS56 (9/21, 42.9%). Genotype-phenotype correlations provided insight into the phenotypic variability among these genes. Particularly, the MFRP-positive group showed a higher tendency to develop peripheral retinal pigmentation while this was rare in the PRSS56- associated group. Moreover, the families with a diagnosis of MCOP had papillomacular folds in common, which was infrequent in families diagnosed with NNO. The identification of new families with MFRP mutations might offer opportunities for potential gene-based therapies.
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author
promoter
UGent, and UGent
organization
year
type
dissertation
publication status
published
subject
pages
227 pages
publisher
Ghent University. Faculty of Medicine and Health Sciences
place of publication
Ghent, Belgium
defense location
Gent : Aula universiteit
defense date
2017-12-08 17:00
language
English
UGent publication?
yes
classification
D1
copyright statement
I have transferred the copyright for this publication to the publisher
id
8541488
handle
http://hdl.handle.net/1854/LU-8541488
date created
2017-12-12 22:39:17
date last changed
2017-12-18 07:41:54
@phdthesis{8541488,
  abstract     = {Vision is one of the most important senses of a human being. It is estimated that 285 million people worldwide suffer from visual impairment. Although the etiology of visual impairment is rather complex, genetic factors play an important role. In this respect, developmental eye disorders have a huge impact on childhood visual impairment and blindness. Here, we focus on three types of developmental eye disorders including: idiopathic infantile nystagmus (IIN), Leber congenital amaurosis (LCA), nanophthalmos and posterior microphthalmia (NNO and MOCP) caused by mutations encoding many different signaling and structural proteins in the developing eye. The pursuit of the molecular diagnosis in these conditions is challenging as they have been hampered by a tremendous clinical and genetic heterogeneity where different modes of Mendelian inheritance can be found.
In the first study of this thesis the role of mutations and copy number variations (CNV) of FRMD7 and GPR143 was investigated in 49 unrelated Belgian probands with a possible diagnosis of X-linked idiopathic infantile nystagmus (XLIIN). Our comprehensive molecular workflow consisted of targeted gene screening using Sanger sequencing and next generation sequencing (NGS), followed by multiplex ligation--dependent probe amplification. This revealed a genetic defect in FRMD7 in 11 of 49 (22.4\%) of the studied probands, including a deletion of 1.29 Mb containing FRMD7 in a syndromic patient with nystagmus and autism spectrum disorder. This study expanded the mutational spectrum of FRMD7 in XLIIN and generated a discovery cohort of IIN patients potentially harboring either hidden genetic variation such as deep intronic or cis-regulatory mutations within FRMD7 or mutations in other genes at known or novel loci.
The second study was targeting 15 consanguineous Saudi families including 20 patients with an initial diagnosis of LCA. A combined approach of homozygosity mapping, targeted gene screening and whole exome sequencing (WES) was applied to unveil the underlying genetic cause in these families. Overall, this strategy identified the causative mutations in all but one (14/15, 93.3\%) of the studied families, guiding refinement of the clinical diagnosis. Specifically, twelve unique homozygous mutations were identified in eight known LCA genes: CABP4, CEP290, CRB1, GUCY2D, MERTK, RDH12, RPGRIP1 and SPATA7. In addition, one novel mutation was found in the recently identified achromatopsia gene ATF6, leading to a clinical diagnosis of achromatopsia in retrospect. Apart from mutations in known disease genes, a homozygous pathogenic variant was found in RIMS2 (Regulating Synaptic Membrane Exocytosis 2) in two affected sibs with LCA and autism spectrum disorder. The expression of RIMS2 in the retina and several brain structures of human, mouse and zebrafish is consistent with the observed phenotype in these sibs. Moreover, RIMS2 is known to play a role in maintaining the photoreceptor ribbon synapse and has been shown previously to be associated with Asperger syndrome, an autism subtype. Interestingly, the paralog RIMS1 was previously shown to be mutated in autosomal dominant cone-rod dystrophy (CORD7) and to be implicated in autism. The identification of RIMS2 as novel candidate gene for LCA and autism link a synaptic protein with autosomal recessive IRD and autism.
Finally, the third study of this doctoral project investigated the role of MFRP and PRSS56 mutations in nanophthalmos (NNO) and posterior microphthalmia (MCOP) in a cohort of 21 unrelated patients from a different ethnic origin. The genetic approach consisted of targeted gene screening and homozygosity mapping in families with a consanguineous background. This revealed the underlying genetic cause in all but two (19/21, 90.5\%) of the studied families, with either homozygous or compound heterozygous distinct mutations in MFRP (10/21, 47.6\%) and PRSS56 (9/21, 42.9\%). Genotype-phenotype correlations provided insight into the phenotypic variability among these genes. Particularly, the MFRP-positive group showed a higher tendency to develop peripheral retinal pigmentation while this was rare in the PRSS56- associated group. Moreover, the families with a diagnosis of MCOP had papillomacular folds in common, which was infrequent in families diagnosed with NNO. The identification of new families with MFRP mutations might offer opportunities for potential gene-based therapies.},
  author       = {Almoallem Mohammed, Basamat},
  language     = {eng},
  pages        = {227},
  publisher    = {Ghent University. Faculty of Medicine and Health Sciences},
  school       = {Ghent University},
  title        = {Unraveling the molecular basis genetically heterogeneous developmental eye disorders},
  year         = {2017},
}

Chicago
Almoallem Mohammed, Basamat. 2017. “Unraveling the Molecular Basis Genetically Heterogeneous Developmental Eye Disorders”. Ghent, Belgium: Ghent University. Faculty of Medicine and Health Sciences.
APA
Almoallem Mohammed, B. (2017). Unraveling the molecular basis genetically heterogeneous developmental eye disorders. Ghent University. Faculty of Medicine and Health Sciences, Ghent, Belgium.
Vancouver
1.
Almoallem Mohammed B. Unraveling the molecular basis genetically heterogeneous developmental eye disorders. [Ghent, Belgium]: Ghent University. Faculty of Medicine and Health Sciences; 2017.
MLA
Almoallem Mohammed, Basamat. “Unraveling the Molecular Basis Genetically Heterogeneous Developmental Eye Disorders.” 2017 : n. pag. Print.