Lars Riff Jensen

Publications of Lars Riff Jensen

• MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression.

  Authors: Suzanna Gerarda Maria Frints, Steffen Lenzner, Mareike Bauters, Lars Riff Jensen, Hilde Van Esch, Vincent des Portes, Ute Moog, Merryn Victor Erik Macville, Kees van Roozendaal, Constance Theresia Rimbertha Maria Schrander-Stumpel [......] Hans van Bokhoven, Jamel Chelly, Chérif Beldjord, Gillian Turner, Jozef Gecz, Claude Moraine, Martine Raynaud, Hans-Hilger Ropers, Guy Froyen, Andreas Walter Kuss

  European journal of human genetics : EJHG. 04/2008;

  Mutations in the thyroid monocarboxylate transporter 8 gene (MCT8/SLC16A2) have been reported to result in X-linked mental retardation (XLMR) in patients with clinical features of theMutations in the thyroid monocarboxylate transporter 8 gene (MCT8/SLC16A2) have been reported to result in X-linked mental retardation (XLMR) in patients with clinical features of the Allan-Herndon-Dudley syndrome (AHDS). We performed MCT8 mutation analysis including 13 XLMR families with LOD scores >2.0, 401 male MR sibships and 47 sporadic male patients with AHDS-like clinical features. One nonsense mutation (c.629insA) and two missense changes (c.1A>T and c.1673G>A) were identified. Consistent with previous reports on MCT8 missense changes, the patient with c.1673G>A showed elevated serum T3 level. The c.1A>T change in another patient affects a putative translation start codon, but the same change was present in his healthy brother. In addition normal serum T3 levels were present, suggesting that the c.1A>T (NM_006517) variation is not responsible for the MR phenotype but indicates that MCT8 translation likely starts with a methionine at position p.75. Moreover, we characterized a de novo translocation t(X;9)(q13.2;p24) in a female patient with full blown AHDS clinical features including elevated serum T3 levels. The MCT8 gene was disrupted at the X-breakpoint. A complete loss of MCT8 expression was observed in a fibroblast cell-line derived from this patient because of unfavorable nonrandom X-inactivation. Taken together, these data indicate that MCT8 mutations are not common in non-AHDS MR patients yet they support that elevated serum T3 levels can be indicative for AHDS and that AHDS clinical features can be present in female MCT8 mutation carriers whenever there is unfavorable nonrandom X-inactivation.European Journal of Human Genetics advance online publication, 9 April 2008; doi:10.1038/ejhg.2008.66.

• A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation.

  Authors: Mohammad Mahdi Motazacker, Benjamin Rainer Rost, Tim Hucho, Masoud Garshasbi, Kimia Kahrizi, Reinhard Ullmann, Seyedeh Sedigheh Abedini, Sahar Esmaeeli Nieh, Saeid Hosseini Amini, Chandan Goswami, Andreas Tzschach, Lars Riff Jensen, Dietmar Schmitz, Hans-Hilger Ropers, Hossein Najmabadi, Andreas Walter Kuss

  American journal of human genetics. 11/2007; 81(4):792-8.

  Nonsyndromic mental retardation is one of the most important unresolved problems in genetic health care. Autosomal forms are far more common than X-linked forms, but, in contrast to the latter, theyNonsyndromic mental retardation is one of the most important unresolved problems in genetic health care. Autosomal forms are far more common than X-linked forms, but, in contrast to the latter, they are still largely unexplored. Here, we report a complex mutation in the ionotropic glutamate receptor 6 gene (GRIK2, also called "GLUR6") that cosegregates with moderate-to-severe nonsyndromic autosomal recessive mental retardation in a large, consanguineous Iranian family. The predicted gene product lacks the first ligand-binding domain, the adjacent transmembrane domain, and the putative pore loop, suggesting a complete loss of function of the GLU(K6) protein, which is supported by electrophysiological data. This finding provides the first proof that GLU(K6) is indispensable for higher brain functions in humans, and future studies of this and other ionotropic kainate receptors will shed more light on the pathophysiology of mental retardation.

• Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium.

  Authors: Arjan P M de Brouwer, Helger G Yntema, Tjitske Kleefstra, Dorien Lugtenberg, Astrid R Oudakker, Bert B A de Vries, Hans van Bokhoven, Hilde Van Esch, Suzanne G M Frints, Guy Froyen [......] Gillian Turner, Tod Fullston, Jozef Gecz, Andreas W Kuss, Andreas Tzschach, Lars Riff Jensen, Steffen Lenzner, Vera M Kalscheuer, Hans-Hilger Ropers, Ben C J Hamel

  Human mutation. 03/2007; 28(2):207-8.

  The EuroMRX family cohort consists of about 400 families with non-syndromic and 200 families with syndromic X-linked mental retardation (XLMR). After exclusion of Fragile X (Fra X) syndrome, probandsThe EuroMRX family cohort consists of about 400 families with non-syndromic and 200 families with syndromic X-linked mental retardation (XLMR). After exclusion of Fragile X (Fra X) syndrome, probands from these families were tested for mutations in the coding sequence of 90 known and candidate XLMR genes. In total, 73 causative mutations were identified in 21 genes. For 42% of the families with obligate female carriers, the mental retardation phenotype could be explained by a mutation. There was no difference between families with (lod score >2) or without (lod score <2) significant linkage to the X chromosome. For families with two to five affected brothers (brother pair=BP families) only 17% of the MR could be explained. This is significantly lower (P=0.0067) than in families with obligate carrier females and indicates that the MR in about 40% (17/42) of the BP families is due to a single genetic defect on the X chromosome. The mutation frequency of XLMR genes in BP families is lower than can be expected on basis of the male to female ratio of patients with MR or observed recurrence risks. This might be explained by genetic risk factors on the X chromosome, resulting in a more complex etiology in a substantial portion of XLMR patients. The EuroMRX effort is the first attempt to unravel the molecular basis of cognitive dysfunction by large-scale approaches in a large patient cohort. Our results show that it is now possible to identify 42% of the genetic defects in non-syndromic and syndromic XLMR families with obligate female carriers.

• X-linked mental retardation: a comprehensive molecular screen of 47 candidate genes from a 7.4 Mb interval in Xp11.

  Authors: Lars Riff Jensen, Steffen Lenzner, Bettina Moser, Kristine Freude, Andreas Tzschach, Chen Wei, Jean-Pierre Fryns, Jamel Chelly, Gillian Turner, Claude Moraine, Ben Hamel, Hans-Hilger Ropers, Andreas Walter Kuss

  European journal of human genetics : EJHG. 02/2007; 15(1):68-75.

  About 30% of the mutations causing nonsyndromic X-linked mental retardation (MRX) are thought to be located in Xp11 and in the pericentromeric region, with a particular clustering of gene defects inAbout 30% of the mutations causing nonsyndromic X-linked mental retardation (MRX) are thought to be located in Xp11 and in the pericentromeric region, with a particular clustering of gene defects in a 7.4 Mb interval flanked by the genes ELK1 and ALAS2. To search for these mutations, 47 brain-expressed candidate genes located in this interval have been screened for mutations in up to 22 mental retardation (MR) families linked to this region. In total, we have identified 57 sequence variants in exons and splice sites of 27 genes. Based on these data, four novel MR genes were identified, but most of the sequence variants observed during this study have not yet been described. The purpose of this article is to present a comprehensive overview of this work and its outcome. It describes all sequence variants detected in 548 exons and their flanking sequences, including disease-causing mutations as well as possibly relevant polymorphic and silent sequence changes. We show that many of the studied genes are unlikely to play a major role in MRX. This information will help to avoid duplication of efforts in the ongoing endeavor to unravel the molecular causes of MRX.

• Novel JARID1C/SMCX mutations in patients with X-linked mental retardation.

  Authors: Andreas Tzschach, Steffen Lenzner, Bettina Moser, Richard Reinhardt, Jamel Chelly, Jean-Pierre Fryns, Tjitske Kleefstra, Martine Raynaud, Gillian Turner, Hans-Hilger Ropers, Andreas Kuss, Lars Riff Jensen

  Human mutation. 05/2006; 27(4):389.

  X-linked mental retardation (XLMR) is a heterogeneous disorder that affects approximately 2 in 1000 males. JARID1C/SMCX is relatively new among the known XLMR genes, and seven different mutationsX-linked mental retardation (XLMR) is a heterogeneous disorder that affects approximately 2 in 1000 males. JARID1C/SMCX is relatively new among the known XLMR genes, and seven different mutations have been identified previously in this gene [Jensen LR et al., Am. J. Hum. Genet. 76:227-236, 2005]. Here, we report five novel JARID1C mutations in five XLMR families. The changes comprise one nonsense mutation (p.Arg332X) and four missense mutations (p.Asp87Gly; p.Phe642Leu; p.Arg750Trp; p.Tyr751Cys) affecting evolutionarily conserved amino acids. The degree of mental retardation in the affected males ranged from mild to severe, and some patients suffered from additional disorders such as epilepsy, short stature, or behavioral problems. This study brings the total number of reported JARID1C mutations to twelve. In contrast to other XLMR genes in which mutations were found only in single or very few families, JARID1C appears to be one of the more frequently mutated genes in this disorder.

• Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males.

  Authors: Hilde Van Esch, Marijke Bauters, Jaakko Ignatius, Mieke Jansen, Martine Raynaud, Karen Hollanders, Dorien Lugtenberg, Thierry Bienvenu, Lars Riff Jensen, Jozef Gecz, Claude Moraine, Peter Marynen, Jean-Pierre Fryns, Guy Froyen

  American journal of human genetics. 10/2005; 77(3):442-53.

  Loss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparativeLoss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparative genomic hybridization (array-CGH), we identified a small duplication at Xq28 in a large family with a severe form of MR associated with progressive spasticity. Screening by real-time quantitation of 17 additional patients with MR who have similar phenotypes revealed three more duplications. The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1CAM and MECP2 genes. The proximal breakpoints are located within a 250-kb region centromeric of L1CAM, whereas the distal breakpoints are located in a 300-kb interval telomeric of MECP2. The precise size and location of each duplication is different in the four patients. The duplications segregate with the disease in the families, and asymptomatic carrier females show complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype. Our findings demonstrate that, in humans, not only impaired or abolished gene function but also increased MeCP2 dosage causes a distinct phenotype. Moreover, duplication of the MECP2 region occurs frequently in male patients with a severe form of MR, which justifies quantitative screening of MECP2 in this group of patients.

• Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation.

  Authors: Lars Riff Jensen, Marion Amende, Ulf Gurok, Bettina Moser, Verena Gimmel, Andreas Tzschach, Andreas R Janecke, Gholamali Tariverdian, Jamel Chelly, Jean-Pierre Fryns, Hilde Van Esch, Tjitske Kleefstra, Ben Hamel, Claude Moraine, Jozef Gecz, Gillian Turner, Richard Reinhardt, Vera M Kalscheuer, Hans-Hilger Ropers, Steffen Lenzner

  American journal of human genetics. 03/2005; 76(2):227-36.

  In families with nonsyndromic X-linked mental retardation (NS-XLMR), >30% of mutations seem to cluster on proximal Xp and in the pericentric region. In a systematic screen of brain-expressed genesIn families with nonsyndromic X-linked mental retardation (NS-XLMR), >30% of mutations seem to cluster on proximal Xp and in the pericentric region. In a systematic screen of brain-expressed genes from this region in 210 families with XLMR, we identified seven different mutations in JARID1C, including one frameshift mutation and two nonsense mutations that introduce premature stop codons, as well as four missense mutations that alter evolutionarily conserved amino acids. In two of these families, expression studies revealed the almost complete absence of the mutated JARID1C transcript, suggesting that the phenotype in these families results from functional loss of the JARID1C protein. JARID1C (Jumonji AT-rich interactive domain 1C), formerly known as "SMCX," is highly similar to the Y-chromosomal gene JARID1D/SMCY, which encodes the H-Y antigen. The JARID1C protein belongs to the highly conserved ARID protein family. It contains several DNA-binding motifs that link it to transcriptional regulation and chromatin remodeling, processes that are defective in various other forms of mental retardation. Our results suggest that JARID1C mutations are a relatively common cause of XLMR and that this gene might play an important role in human brain function.

• Mutations in the FTSJ1 gene coding for a novel S-adenosylmethionine-binding protein cause nonsyndromic X-linked mental retardation.

  Authors: Kristine Freude, Kirsten Hoffmann, Lars Riff Jensen, Martin B Delatycki, Vincent des Portes, Bettina Moser, Ben Hamel, Hans van Bokhoven, Claude Moraine, Jean-Pierre Fryns, Jamel Chelly, Jozef Gécz, Steffen Lenzner, Vera M Kalscheuer, Hans-Hilger Ropers

  American journal of human genetics. 09/2004; 75(2):305-9.

  Nonsyndromic X-linked mental retardation (NSXLMR) is a very heterogeneous condition, and most of the underlying gene defects are still unknown. Recently, we have shown that approximately 30% of theseNonsyndromic X-linked mental retardation (NSXLMR) is a very heterogeneous condition, and most of the underlying gene defects are still unknown. Recently, we have shown that approximately 30% of these genes cluster on the proximal Xp, which prompted us to perform systematic mutation screening in brain-expressed genes from this region. Here, we report on a novel NSXLMR gene, FTSJ1, which harbors mutations in three unrelated families--one with a splicing defect, one with a nonsense mutation, and one with a deletion of one nucleotide. In two families, subsequent expression studies showed complete absence or significant reduction of mutant FTSJ1 transcripts. FTSJ1 protein is a homolog of Escherichia coli RNA methyltransferase FtsJ/RrmJ and may play a role in the regulation of translation. Further studies aim to elucidate the function of human FTSJ1 and its role during brain development.

• Genomic structure, chromosome mapping and expression analysis of the human AVIL gene, and its exclusion as a candidate for locus for inflammatory bowel disease at 12q13-14 (IBD2).

  Authors: Zeynep Tümer, Peter J P Croucher, Lars Riff Jensen, Jochen Hampe, Claus Hansen, Vera Kalscheuer, Hans-Hilger Ropers, Niels Tommerup, Stefan Schreiber

  Gene. 05/2002; 288(1-2):179-85.

  Chronic inflammatory bowel disease is a multifactorial disorder with two major clinical forms, Crohn's disease and ulcerative colitis. One of the potential susceptibility loci for inflammatory bowelChronic inflammatory bowel disease is a multifactorial disorder with two major clinical forms, Crohn's disease and ulcerative colitis. One of the potential susceptibility loci for inflammatory bowel disease (IBD2) was localized at 12q13-14 in the vicinity of the deoxyribonucleic acid marker D12S83 by linkage analysis. A candidate susceptibility gene for IBD2 in this region is the AVIL gene. AVIL encodes a protein (advillin) which belongs to the gelsolin/villin family of proteins and might therefore be involved in morphogenesis of microvilli. We have determined the genomic organization of the AVIL gene, including the transcription start site and its localization with respect to D12S83. The 2457 bp coding region of AVIL consists of 19 exons and is localized to 12q14 proximal to D12S83. Primer extension analysis suggests two transcription start sites localized at -548 and -664 bp upstream to the ATG translation codon. We have evaluated AVIL as a candidate susceptibility gene for IBD2 in 24 unrelated patients with evidence of linkage to chromosome 12, as well as in 91 individuals from 19 affected IBD families for putative single nucleotide polymorphisms.

• Mutations in the JARID1C Gene, Which Is Involved in Transcriptional Regulation and Chromatin Remodeling, Cause X-Linked Mental Retardation

  Authors: Lars Riff Jensen, Marion Amende, Ulf Gurok, Bettina Moser, Verena Gimmel, Andreas Tzschach, Andreas R Janecke, Gholamali Tariverdian, Jamel Chelly, Jean-Pierre Fryns, Hilde Van Esch, Tjitske Kleefstra, Ben Hamel, Claude Moraine, Jozef Gécz, Gillian Turner, Richard Reinhardt, Vera M Kalscheuer, Hans-Hilger Ropers, Steffen Lenzner

  In families with nonsyndromic X-linked mental retardation (NS-XLMR), >30% of mutations seem to cluster on proximal Xp and in the pericentric region. In a systematic screen of brain-expressed genesIn families with nonsyndromic X-linked mental retardation (NS-XLMR), >30% of mutations seem to cluster on proximal Xp and in the pericentric region. In a systematic screen of brain-expressed genes from this region in 210 families with XLMR, we identified seven different mutations in JARID1C, including one frameshift mutation and two nonsense mutations that introduce premature stop codons, as well as four missense mutations that alter evolutionarily conserved amino acids. In two of these families, expression studies revealed the almost complete absence of the mutated JARID1C transcript, suggesting that the phenotype in these families results from functional loss of the JARID1C protein. JARID1C (Jumonji AT-rich interactive domain 1C), formerly known as “SMCX,” is highly similar to the Y-chromosomal gene JARID1D/SMCY, which encodes the H-Y antigen. The JARID1C protein belongs to the highly conserved ARID protein family. It contains several DNA-binding motifs that link it to transcriptional regulation and chromatin remodeling, processes that are defective in various other forms of mental retardation. Our results suggest that JARID1C mutations are a relatively common cause of XLMR and that this gene might play an important role in human brain function.

• Duplication of the MECP2 Region Is a Frequent Cause of Severe Mental Retardation and Progressive Neurological Symptoms in Males

  Authors: Hilde Van Esch, Marijke Bauters, Jaakko Ignatius, Mieke Jansen, Martine Raynaud, Karen Hollanders, Dorien Lugtenberg, Thierry Bienvenu, Lars Riff Jensen, Jozef Gécz, Claude Moraine, Peter Marynen, Jean-Pierre Fryns, Guy Froyen

  Loss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparativeLoss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparative genomic hybridization (array-CGH), we identified a small duplication at Xq28 in a large family with a severe form of MR associated with progressive spasticity. Screening by real-time quantitation of 17 additional patients with MR who have similar phenotypes revealed three more duplications. The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1CAM and MECP2 genes. The proximal breakpoints are located within a 250-kb region centromeric of L1CAM, whereas the distal breakpoints are located in a 300-kb interval telomeric of MECP2. The precise size and location of each duplication is different in the four patients. The duplications segregate with the disease in the families, and asymptomatic carrier females show complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype. Our findings demonstrate that, in humans, not only impaired or abolished gene function but also increased MeCP2 dosage causes a distinct phenotype. Moreover, duplication of the MECP2 region occurs frequently in male patients with a severe form of MR, which justifies quantitative screening of MECP2 in this group of patients.