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Dive into the research topics where Richard J.L.F. Lemmers is active.

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Featured researches published by Richard J.L.F. Lemmers.


Science | 2010

A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy

Richard J.L.F. Lemmers; Patrick J. van der Vliet; Rinse Klooster; Sabrina Sacconi; Pilar Camaño; Johannes G. Dauwerse; Lauren Snider; Kirsten R. Straasheijm; Gert Jan B. van Ommen; George W. Padberg; Daniel G. Miller; Stephen J. Tapscott; Rabi Tawil; Rune R. Frants; Silvère M. van der Maarel

Addition by Contraction Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common hereditary neuromuscular disorders in Western populations, affecting about 1 in 20,000 people. In most patients, the disorder is associated with contraction of a D4Z4 microsatellite repeat array on chromosome 4q, but this contraction can also occur in the absence of disease, so the underlying genetic mechanisms have remained elusive. Lemmers et al. (p. 1650, published online 19 August; see the Perspective by Mahadevan) now show that FSHD patients carry sequence variants that create a canonical polyadenylation signal for transcripts derived from DUX4, a homeobox gene straddling the last D4Z4 repeat unit and the adjacent sequence. Addition of poly(A) stabilizes the DUX4 transcript, which is likely to be a contributing factor in the disease. Sequence variants shared by patients with a genetically complex form of muscular dystrophy explain how the disease arises. Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy in adults that is foremost characterized by progressive wasting of muscles in the upper body. FSHD is associated with contraction of D4Z4 macrosatellite repeats on chromosome 4q35, but this contraction is pathogenic only in certain “permissive” chromosomal backgrounds. Here, we show that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. These findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript.


Nature Genetics | 2001

Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter

P.A.J. Leegwater; Gerre Vermeulen; Andrea A.M. Könst; Sakkubai Naidu; Joyce Mulders; Allerdien Visser; Paula Kersbergen; Dragosh Mobach; Dafna Fonds; Carola G.M. van Berkel; Richard J.L.F. Lemmers; Rune R. Frants; Cees B.M. Oudejans; Ruud B.H. Schutgens; Jan C. Pronk; Marjo S. van der Knaap

Leukoencephalopathy with vanishing white matter (VWM) is an inherited brain disease that occurs mainly in children. The course is chronic-progressive with additional episodes of rapid deterioration following febrile infection or minor head trauma. We have identified mutations in EIF2B5 and EIF2B2, encoding the ɛ- and β-subunits of the translation initiation factor eIF2B and located on chromosomes 3q27 and 14q24, respectively, as causing VWM. We found 16 different mutations in EIF2B5 in 29 patients from 23 families. We also found two distantly related individuals who were homozygous with respect to a missense mutation in EIF2B2, affecting a conserved amino acid. Three other patients also had mutations in EIF2B2. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, this may explain the rapid deterioration of people with VWM under stress. Mutant translation initiation factors have not previously been implicated in disease.


Nature Genetics | 2012

Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2

Richard J.L.F. Lemmers; Rabi Tawil; Lisa M. Petek; Judit Balog; Gregory J. Block; Gijs W.E. Santen; Amanda M. Amell; Patrick J. van der Vliet; Rowida Almomani; Kirsten R. Straasheijm; Yvonne D. Krom; Rinse Klooster; Yu-chun Sun; Johan T. den Dunnen; Quinta Helmer; Colleen M. Donlin-Smith; George W. Padberg; Baziel G.M. van Engelen; Jessica C. de Greef; Annemieke Aartsma-Rus; Rune R. Frants; Marianne de Visser; Claude Desnuelle; Sabrina Sacconi; Galina N. Filippova; Bert Bakker; Michael J. Bamshad; Stephen J. Tapscott; Daniel G. Miller; Silvère M. van der Maarel

Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction–independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction–independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.


PLOS Genetics | 2010

Facioscapulohumeral Dystrophy: Incomplete Suppression of a Retrotransposed Gene

Lauren Snider; Linda N. Geng; Richard J.L.F. Lemmers; Michael Kyba; Carol B. Ware; Angelique M. Nelson; Rabi Tawil; Galina N. Filippova; Silvère M. van der Maarel; Stephen J. Tapscott; Daniel G. Miller

Each unit of the D4Z4 macrosatellite repeat contains a retrotransposed gene encoding the DUX4 double-homeobox transcription factor. Facioscapulohumeral dystrophy (FSHD) is caused by deletion of a subset of the D4Z4 units in the subtelomeric region of chromosome 4. Although it has been reported that the deletion of D4Z4 units induces the pathological expression of DUX4 mRNA, the association of DUX4 mRNA expression with FSHD has not been rigorously investigated, nor has any human tissue been identified that normally expresses DUX4 mRNA or protein. We show that FSHD muscle expresses a different splice form of DUX4 mRNA compared to control muscle. Control muscle produces low amounts of a splice form of DUX4 encoding only the amino-terminal portion of DUX4. FSHD muscle produces low amounts of a DUX4 mRNA that encodes the full-length DUX4 protein. The low abundance of full-length DUX4 mRNA in FSHD muscle cells represents a small subset of nuclei producing a relatively high abundance of DUX4 mRNA and protein. In contrast to control skeletal muscle and most other somatic tissues, full-length DUX4 transcript and protein is expressed at relatively abundant levels in human testis, most likely in the germ-line cells. Induced pluripotent (iPS) cells also express full-length DUX4 and differentiation of control iPS cells to embryoid bodies suppresses expression of full-length DUX4, whereas expression of full-length DUX4 persists in differentiated FSHD iPS cells. Together, these findings indicate that full-length DUX4 is normally expressed at specific developmental stages and is suppressed in most somatic tissues. The contraction of the D4Z4 repeat in FSHD results in a less efficient suppression of the full-length DUX4 mRNA in skeletal muscle cells. Therefore, FSHD represents the first human disease to be associated with the incomplete developmental silencing of a retrogene array normally expressed early in development.


Nature Genetics | 2002

Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere.

Richard J.L.F. Lemmers; Peggy de Kievit; Lodewijk A. Sandkuijl; George W. Padberg; Gert-Jan B. van Ommen; Rune R. Frants; Silvère M. van der Maarel

Contractions in the polymorphic D4Z4 repeat array of subtelomere 4qter cause autosomal dominant facioscapulohumeral muscular dystrophy in humans. A polymorphic segment of 10 kb directly distal to D4Z4 exists in two allelic forms, 4qA and 4qB. Although both alleles are equally common in the general population, we now report that FSHD is associated solely with the 4qA allele.


American Journal of Human Genetics | 2007

Specific Sequence Variations within the 4q35 Region Are Associated with Facioscapulohumeral Muscular Dystrophy

Richard J.L.F. Lemmers; M. Wohlgemuth; Kristiaan J. van der Gaag; Patrick J. van der Vliet; Corrie M.M. van Teijlingen; Peter de Knijff; George W. Padberg; Rune R. Frants; Silvère M. van der Maarel

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is mainly characterized by progressive wasting and weakness of the facial, shoulder, and upper-arm muscles. FSHD is caused by contraction of the macrosatellite repeat D4Z4 on chromosome 4q35. The D4Z4 repeat is very polymorphic in length, and D4Z4 rearrangements occur almost exclusively via intrachromosomal gene conversions. Several disease mechanisms have been proposed, but none of these models can comprehensively explain FSHD, because repeat contraction alone is not sufficient to cause disease. Almost-identical D4Z4-repeat arrays have been identified on chromosome 10q26 and on two equally common chromosome 4 variants, 4qA and 4qB. Yet only repeat contractions of D4Z4 on chromosome 4qA cause FSHD; contractions on the other chromosomes are nonpathogenic. We hypothesized that allele-specific sequence differences among 4qA, 4qB, and 10q alleles underlie the 4qA specificity of FSHD. Sequence variations between these alleles have been described before, but the extent and significance of these variations proximal to, within, and distal to D4Z4 have not been studied in detail. We examined additional sequence variations in the FSHD locus, including a relatively stable simple sequence-length polymorphism proximal to D4Z4, a single-nucleotide polymorphism (SNP) within D4Z4, and the A/B variation distal to D4Z4. On the basis of these polymorphisms, we demonstrate that the subtelomeric domain of chromosome 4q can be subdivided into nine distinct haplotypes, of which three carry the distal 4qA variation. Interestingly, we show that repeat contractions in two of the nine haplotypes, one of which is a 4qA haplotype, are not associated with FSHD. We also show that each of these haplotypes has its unique sequence signature, and we propose that specific SNPs in the disease haplotype are essential for the development of FSHD.


Human Molecular Genetics | 2009

RNA Transcripts, miRNA-sized Fragments, and Proteins Produced from D4Z4 Units: New Candidates for the Pathophysiology of Facioscapulohumeral Dystrophy

Lauren Snider; Amy Asawachaicharn; Ashlee E. Tyler; Linda N. Geng; Lisa M. Petek; Lisa Maves; Daniel G. Miller; Richard J.L.F. Lemmers; Sara T. Winokur; Rabi Tawil; Silvère M. van der Maarel; Galina N. Filippova; Stephen J. Tapscott

Deletion of a subset of the D4Z4 macrosatellite repeats in the subtelomeric region of chromosome 4q causes facioscapulohumeral muscular dystrophy (FSHD) when occurring on a specific haplotype of 4qter (4qA161). Several genes have been examined as candidates for causing FSHD, including the DUX4 homeobox gene in the D4Z4 repeat, but none have been definitively shown to cause the disease, nor has the full extent of transcripts from the D4Z4 region been carefully characterized. Using strand-specific RT-PCR, we have identified several sense and antisense transcripts originating from the 4q D4Z4 units in wild-type and FSHD muscle cells. Consistent with prior reports, we find that the DUX4 transcript from the last (most telomeric) D4Z4 unit is polyadenylated and has two introns in its 3-prime untranslated region. In addition, we show that this transcript generates (i) small si/miRNA-sized fragments, (ii) uncapped, polyadenylated 3-prime fragments that encode the conserved C-terminal portion of DUX4 and (iii) capped and polyadenylated mRNAs that contain the double-homeobox domain of DUX4 but splice-out the C-terminal portion. Transfection studies demonstrate that translation initiation at an internal methionine can produce the C-terminal polypeptide and developmental studies show that this peptide inhibits myogenesis at a step between MyoD transcription and the activation of MyoD target genes. Together, we have identified new sense and anti-sense RNA transcripts, novel mRNAs and mi/siRNA-sized RNA fragments generated from the D4Z4 units that are new candidates for the pathophysiology of FSHD.


Human Mutation | 2009

Common epigenetic changes of D4Z4 in contraction‐dependent and contraction‐independent FSHD

Jessica C. de Greef; Richard J.L.F. Lemmers; Baziel G.M. van Engelen; Sabrina Sacconi; Shannon L. Venance; Rune R. Frants; Rabi Tawil; Silvère M. van der Maarel

Facioscapulohumeral muscular dystrophy (FSHD), caused by partial deletion of the D4Z4 macrosatellite repeat on chromosome 4q, has a complex genetic and epigenetic etiology. To develop FSHD, D4Z4 contraction needs to occur on a specific genetic background. Only contractions associated with the 4qA161 haplotype cause FSHD. In addition, contraction of the D4Z4 repeat in FSHD patients is associated with significant D4Z4 hypomethylation. To date, however, the methylation status of contracted repeats on nonpathogenic haplotypes has not been studied. We have performed a detailed methylation study of the D4Z4 repeat on chromosome 4q and on a highly homologous repeat on chromosome 10q. We show that patients with a D4Z4 deletion (FSHD1) have D4Z4‐restricted hypomethylation. Importantly, controls with a D4Z4 contraction on a nonpathogenic chromosome 4q haplotype or on chromosome 10q also demonstrate hypomethylation. In 15 FSHD families without D4Z4 contractions but with at least one 4qA161 haplotype (FSHD2), we observed D4Z4‐restricted hypomethylation on chromosomes 4q and 10q. This finding implies that a genetic defect resulting in D4Z4 hypomethylation underlies FSHD2. In conclusion, we describe two ways to develop FSHD: (1) contraction‐dependent or (2) contraction‐independent D4Z4 hypomethylation on the 4qA161 subtelomere. Hum Mutat 30:1–11, 2009.


Neurology | 2010

Clinical features of facioscapulohumeral muscular dystrophy 2.

J.C. de Greef; Richard J.L.F. Lemmers; Pilar Camaño; John W. Day; S. Sacconi; M. Dunand; B.G.M. van Engelen; Sari Kiuru-Enari; G.W.A.M. Padberg; A.L. Rosa; Claude Desnuelle; Simone Spuler; M. Tarnopolsky; Shannon L. Venance; Rune R. Frants; S.M. van der Maarel; Rabi Tawil

Objective: In some 5% of patients with facioscapulohumeral muscular dystrophy (FSHD), no D4Z4 repeat contraction on chromosome 4q35 is observed. Such patients, termed patients with FSHD2, show loss of DNA methylation and heterochromatin markers at the D4Z4 repeat that are similar to patients with D4Z4 contractions (FSHD1). This commonality suggests that a change in D4Z4 chromatin structure unifies FSHD1 and FSHD2. The aim of our study was to critically evaluate the clinical features in patients with FSHD2 in order to establish whether these patients are phenotypically identical to FSHD1 and to establish the effects of the (epi-) genotype on the phenotype. Methods: This cross-sectional study studied 33 patients with FSHD2 from 27 families, the largest cohort described to date. All patients were clinically assessed using a standardized clinical evaluation form. Genotype analysis was performed by pulsed field gel electrophoresis and PCR; D4Z4 methylation was studied by methylation-sensitive Southern blot analysis. Results: FSHD2 is identical to FSHD1 in its clinical presentation. Notable differences include a higher incidence (67%) of sporadic cases and the absence of gender differences in disease severity in FSHD2. Overall, average disease severity in FSHD2 was similar to that reported in FSHD1 and was not influenced by D4Z4 repeat size. In FSHD2, a small effect of the degree of hypomethylation on disease severity was observed. Conclusions: Clinically, patients with FSHD2 are indistinguishable from patients with FSHD1. The present data suggest that FSHD1 and FSHD2 are the result of the same pathophysiologic process.


American Journal of Human Genetics | 2000

De Novo Facioscapulohumeral Muscular Dystrophy: Frequent Somatic Mosaicism, Sex-Dependent Phenotype, and the Role of Mitotic Transchromosomal Repeat Interaction between Chromosomes 4 and 10

Silvère M. van der Maarel; Giancarlo Deidda; Richard J.L.F. Lemmers; Petra G.M. van Overveld; Michiel van der Wielen; Jane E. Hewitt; Lodewijk A. Sandkuijl; Bert Bakker; Gert-Jan B. van Ommen; George W. Padberg; Rune R. Frants

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is caused by deletion of most copies of the 3.3-kb subtelomeric D4Z4 repeat array on chromosome 4q. The molecular mechanisms behind the deletion and the high proportion of new mutations have remained elusive. We surveyed 35 de novo FSHD families and found somatic mosaicism in 40% of cases, in either the patient or an asymptomatic parent. Mosaic males were typically affected; mosaic females were more often the unaffected parent of a nonmosaic de novo patient. A genotypic-severity score, composed of the residual repeat size and the degree of somatic mosaicism, yields a consistent relationship with severity and age at onset of disease. Mosaic females had a higher proportion of somatic mosaicism than did mosaic males. The repeat deletion is significantly enhanced by supernumerary homologous repeat arrays. In 10% of normal chromosomes, 4-type repeat arrays are present on chromosome 10. In mosaic individuals, 4-type repeats on chromosome 10 are almost five times more frequent. The reverse configuration, also 10% in normal chromosomes, was not found, indicating that mutations may arise from transchromosomal interaction, to which the increase in 4-type repeat clusters is a predisposing factor. The somatic mosaicism suggests a mainly mitotic origin; mitotic interchromosomal gene conversion or translocation between fully homologous 4-type repeat arrays may be a major mechanism for FSHD mutations.

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Silvère M. van der Maarel

Leiden University Medical Center

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Rune R. Frants

Leiden University Medical Center

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Rabi Tawil

University of Rochester Medical Center

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Stephen J. Tapscott

Fred Hutchinson Cancer Research Center

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George W. Padberg

Radboud University Nijmegen

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Patrick J. van der Vliet

Leiden University Medical Center

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S.M. van der Maarel

Leiden University Medical Center

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Judit Balog

Leiden University Medical Center

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Sabrina Sacconi

University of Nice Sophia Antipolis

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