Person: Haghighi, Alireza
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Haghighi
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Alireza
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Haghighi, Alireza
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Publication The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease(BMJ Publishing Group, 2016) Ng, Yi Shiau; Alston, Charlotte L; Diodato, Daria; Morris, Andrew A; Ulrick, Nicole; Kmoch, Stanislav; Houštěk, Josef; Martinelli, Diego; Haghighi, Alireza; Atiq, Mehnaz; Gamero, Montserrat Anton; Garcia-Martinez, Elena; Kratochvílová, Hana; Santra, Saikat; Brown, Ruth M; Brown, Garry K; Ragge, Nicola; Monavari, Ahmad; Pysden, Karen; Ravn, Kirstine; Casey, Jillian P; Khan, Arif; Chakrapani, Anupam; Vassallo, Grace; Simons, Cas; McKeever, Karl; O'Sullivan, Siobhan; Childs, Anne-Marie; Østergaard, Elsebet; Vanderver, Adeline; Goldstein, Amy; Vogt, Julie; Taylor, Robert W; McFarland, RobertBackground: Mutations in the RMND1 (Required for Meiotic Nuclear Division protein 1) gene have recently been linked to infantile onset mitochondrial disease characterised by multiple mitochondrial respiratory chain defects. Methods: We summarised the clinical, biochemical and molecular genetic investigation of an international cohort of affected individuals with RMND1 mutations. In addition, we reviewed all the previously published cases to determine the genotype–phenotype correlates and performed survival analysis to identify prognostic factors. Results: We identified 14 new cases from 11 pedigrees that harbour recessive RMND1 mutations, including 6 novel variants: c.533C>A, p.(Thr178Lys); c.565C>T, p.(Gln189*); c.631G>A, p.(Val211Met); c.1303C>T, p.(Leu435Phe); c.830+1G>A and c.1317+1G>T. Together with all previously published cases (n=32), we show that congenital sensorineural deafness, hypotonia, developmental delay and lactic acidaemia are common clinical manifestations with disease onset under 2 years. Renal involvement is more prevalent than seizures (66% vs 44%). In addition, median survival time was longer in patients with renal involvement compared with those without renal disease (6 years vs 8 months, p=0.009). The neurological phenotype also appears milder in patients with renal involvement. Conclusions: The clinical phenotypes and prognosis associated with RMND1 mutations are more heterogeneous than that were initially described. Regular monitoring of kidney function is imperative in the clinical practice in light of nephropathy being present in over 60% of cases. Furthermore, renal replacement therapy should be considered particularly in those patients with mild neurological manifestation as shown in our study that four recipients of kidney transplant demonstrate good clinical outcome to date.Publication A Novel Missense Mutation in Oncostatin M Receptor Beta Causing Primary Localized Cutaneous Amyloidosis(Hindawi Publishing Corporation, 2014) Saeedi, Marjan; Ebrahim-Habibi, Azadeh; Haghighi, Alireza; Zarrabi, Fariba; Amoli, Mahsa M.; Robati, Reza M.Primary localized cutaneous amyloidosis (PLCA) is a chronic skin disorder, caused by amyloid material deposition in the upper dermis. Autosomal dominant PLCA has been mapped earlier to pathogenic missense mutations in the OSMR gene, which encodes the oncostatin M receptor ß subunit (OSMRß). OSMRß is interleukin-6 family cytokine receptors and possesses two ligands, oncostatin M and interleukin-31, which both have biologic roles in inflammation and keratinocyte cell proliferation, differentiation, and apoptosis. Here, we identified a new OSMR mutation in a Kurdish family for the first time. Blood samples were taken from all the affected individuals in the family. DNA extraction was performed using salting out technique. Primers were designed for intron flanking individual exons of OSMR gene which were subjected to direct sequencing after PCR amplification for each sample. Sequencing showed a C/T substitution at position 613 in the proband. This mutation results in an L613S (leucine 613 to serine) amino acid change. The identified mutation was observed in all affected family members but not in 100 ethnically matched healthy controls. Elucidating the molecular basis of familial PLCA provides new insight into mechanisms of itch in human skin and may lead to new therapeutic targets for pruritus.Publication Sengers syndrome: six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients(BioMed Central, 2014) Haghighi, Alireza; Haack, Tobias B; Atiq, Mehnaz; Mottaghi, Hassan; Haghighi-Kakhki, Hamidreza; Bashir, Rani A; Ahting, Uwe; Feichtinger, René G; Mayr, Johannes A; Rötig, Agnès; Lebre, Anne-Sophie; Klopstock, Thomas; Dworschak, Andrea; Pulido, Nathan; Saeed, Mahmood A; Saleh-Gohari, Nasrollah; Holzerova, Eliska; Chinnery, Patrick F; Taylor, Robert W; Prokisch, HolgerBackground: Sengers syndrome is an autosomal recessive condition characterized by congenital cataract, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. Mutations in the acylglycerol kinase (AGK) gene have been recently described as the cause of Sengers syndrome in nine families. Methods: We investigated the clinical and molecular features of Sengers syndrome in seven new families; five families with the severe and two with the milder form. Results: Sequence analysis of AGK revealed compound heterozygous or homozygous predicted loss-of-function mutations in all affected individuals. A total of eight different disease alleles were identified, of which six were novel, homozygous c.523_524delAT (p.Ile175Tyrfs*2), c.424-1G > A (splice site), c.409C > T (p.Arg137*) and c.877 + 3G > T (splice site), and compound heterozygous c.871C > T (p.Gln291*) and c.1035dup (p.Ile346Tyrfs*39). All patients displayed perinatal or early-onset cardiomyopathy and cataract, clinical features pathognomonic for Sengers syndrome. Other common findings included blood lactic acidosis and tachydyspnoea while nystagmus, eosinophilia and cervical meningocele were documented in only either one or two cases. Deficiency of the adenine nucleotide translocator was found in heart and skeletal muscle biopsies from two patients associated with respiratory chain complex I deficiency. In contrast to previous findings, mitochondrial DNA content was normal in both tissues. Conclusion: We compare our findings to those in 21 previously reported AGK mutation-positive Sengers patients, confirming that Sengers syndrome is a clinically recognisable disorder of mitochondrial energy metabolism.Publication Characterization of CSF2RA mutation related juvenile pulmonary alveolar proteinosis(BioMed Central, 2014) Hildebrandt, Jenna; Yalcin, Ebru; Bresser, Hans-Georg; Cinel, Guzin; Gappa, Monika; Haghighi, Alireza; Kiper, Nural; Khalilzadeh, Soheila; Reiter, Karl; Sayer, John; Schwerk, Nicolaus; Sibbersen, Anke; Van Daele, Sabine; Nübling, Georg; Lohse, Peter; Griese, MatthiasBackground: Juvenile pulmonary alveolar proteinosis (PAP) due to CSF2RA mutations is a rare disorder with only a few cases described worldwide. Methods: We identified nine children with severe diffuse interstitial lung disease due to CSF2RA mutations. Clinical course, diagnostic findings and treatment were evaluated and correlated to the genotype. Functional impairment of the intracellular JAK/pStat5 signaling pathway was assessed using flow-cytometry of peripheral mononuclear cells (PBMC) and granulocytes. Results: We identified six individuals with homozygous missense/nonsense/frameshift mutations and three individuals homozygous for a deletion of the complete CSF2RA gene locus. Overall, four novel mutations (c.1125 + 1G > A, duplication exon 8, deletion exons 2–13, Xp22.3/Yp11.3) were found. Reduced STAT5 phosphorylation in PBMC and granulocytes was seen in all cases examined (n = 6). Pulmonary symptoms varied from respiratory distress to clinically silent. Early disease onset was associated with a more severe clinical phenotype (p = 0.0092). No association was seen between severity of phenotype at presentation and future clinical course or extent of genetic damage. The clinical course was favorable in all subjects undergoing whole lung lavage (WLL) treatment. Conclusions: Our cohort broadens the spectrum of knowledge about the clinical variability and genotype-phenotype correlations of juvenile PAP, and illustrates the favorable outcome of WLL treatment in severely affected patients. Electronic supplementary material The online version of this article (doi:10.1186/s13023-014-0171-z) contains supplementary material, which is available to authorized users.Publication Homozygosity Mapping and Whole Exome Sequencing Reveal a Novel Homozygous COL18A1 Mutation Causing Knobloch Syndrome(Public Library of Science, 2014) Haghighi, Alireza; Tiwari, Amit; Piri, Niloofar; Nürnberg, Gudrun; Saleh-Gohari, Nasrollah; Haghighi, Amirreza; Neidhardt, John; Nürnberg, Peter; Berger, WolfgangThe aim of this study was to identify the genetic basis of a chorioretinal dystrophy with high myopia of unknown origin in a child of a consanguineous marriage. The proband and ten family members of Iranian ancestry participated in this study. Linkage analysis was carried out with DNA samples of the proband and her parents by using the Human SNP Array 6.0. Whole exome sequencing (WES) was performed with the patients’ DNA. Specific sequence alterations within the homozygous regions identified by whole exome sequencing were verified by Sanger sequencing. Upon genetic analysis, a novel homozygous frameshift mutation was found in exon 42 of the COL18A1 gene in the patient. Both parents were heterozygous for this sequence variation. Mutations in COL18A1 are known to cause Knobloch syndrome (KS). Retrospective analysis of clinical records of the patient revealed surgical removal of a meningocele present at birth. The clinical features shown by our patient were typical of KS with the exception of chorioretinal degeneration which is a rare manifestation. This is the first case of KS reported in a family of Iranian ancestry. We identified a novel disease-causing (deletion) mutation in the COL18A1 gene leading to a frameshift and premature stop codon in the last exon. The mutation was not present in SNP databases and was also not found in 192 control individuals. Its localization within the endostatin domain implicates a functional relevance of endostatin in KS. A combined approach of linkage analysis and WES led to a rapid identification of the disease-causing mutation even though the clinical description was not completely clear at the beginning.Publication Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy(American Association for the Advancement of Science (AAAS), 2015) Hinson, John Travis; Chopra, Anant; Nafissi, N.; Polacheck, William J.; Benson, Craig Carlyle; Swist, S.; Gorham, Joshua; Yang, Luhan; Schafer, S.; Sheng, Calvin Chen; Haghighi, Alireza; Homsy, Jason; Hubner, N.; Church, George; Cook, S. A.; Linke, Wolfgang; Chen, Christopher; Seidman, Jonathan; Seidman, ChristineHuman mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell–derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.