Biomedical subjects

Richard J L F Lemmers

Publications and source records attributed to Richard J L F Lemmers.

7 recordsLinked to original sources

PubMed2026

The emergence and diversification of the DUX gene family across placental mammals.

The DUX gene family encodes transcription factors with paired homeodomains. It has critical roles in embryogenesis and disease, including facioscapulohumeral muscular dystrophy (FSHD) and cancer. This study conducts a comparative analysis of the DUX gene family-DUXA, DUXB (including DUXBL), and DUXC (including DUX4 and Dux)-across placental mammals, highlighting their structural diversity within macrosatellite repeat contexts. Using long-read genomes, we explore gene distribution, array patterns, and phylogenetic relationships in various vertebrate species. Our analysis reveals that DUXA and DUXB are highly conserved, with intriguing variations such as intronless forms likely arising from ancestral retrotransposition events. While DUXBL is inconsistently retained across clades, its locus-which in non-placental mammals harbors the ancestral single-homeodomain sDUX gene-served as an evolutionary hub for diversification, giving rise to DUXA, DUXB and DUXC, as well as macrosatellite tandem array structures. Sequence conservation and syntenic analyses demonstrate array adaptability, exemplified by higher-order repeats in orangutans and disrupted patterns of concerted evolution in elephants. Furthermore, analysis of human pseudo-DUX4 arrays indicates their potential role in disease mechanisms, including as possible contributors to rare cases of FSHD, warranting further investigation. This study thus provides insights into DUX-family gene evolution, offering a foundation for future research into developmental roles and disease implications.

Animals↗

PubMed2005

Equal proportions of affected cells in muscle and blood of a mosaic carrier of facioscapulohumeral muscular dystrophy.

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is associated with contractions of D4Z4 repeat on 4q35. It displays a remarkable inter- and intra-familial clinical variability ranging from severe phenotype to asymptomatic carriers. Mosaicism for the contracted FSHD-sized allele is a recurrent finding, but only DNA from lymphocytes had been studied. It is currently not known if mosaicism is unequally distributed between different tissues and if muscle is relatively spared for the presence of the disease allele in mosaic asymptomatic carriers of a disease allele. Here we compare DNA extracted from peripheral blood lymphocytes (PBL), fibroblasts and muscle from a mosaic asymptomatic female carrier and mother of a FSHD patient. PFGE analysis showed a complex allelic segregation: two independent mitotic rearrangement episodes occurred, resulting in mosaicism for a contracted D4Z4 repeat on 4q35 in the mother and mosaicism for an expanded D4Z4 repeat on 10q26 in the affected daughter. The results show that the proportion of mosaicism in PBL and muscle were comparable, while in fibroblasts there was some variation in the mosaicism, which might be caused by culturing artefacts. This finding supports the hypothesis that a mitotic contraction of D4Z4 is an early embryonic event and indicates that the degree of mosaicism in PBL is representative for that of muscle.

Alleles↗

PubMed2005

Genetic confirmation of facioscapulohumeral muscular dystrophy in a case with complex D4Z4 rearrangments.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of the D4Z4 repeat on chromosome 4q. Genetic confirmation of the clinical diagnosis of FSHD is complicated by the presence of a homologous repeat on chromosome 10q and the frequent repeat exchanges between both chromosomes. Here, we describe the genetic evaluation of an FSHD patient with a complex D4Z4 allele constitution in which the potentially pathogenic allele seemingly resides on chromosome 10, despite FSHD being exclusively linked to chromosome 4. Complementary allele typing and segregation analysis confirmed the clinical diagnosis of FSHD by revealing the chromosome 4 origin of the pathogenic allele in the presence of two exchanged repeat arrays, one on chromosome 4 and one on chromosome 10, an allele constitution that cannot be identified by conventional DNA diagnosis.

Aged↗

PubMed2005

Recurrent somatic mosaicism for D4Z4 contractions in a family with facioscapulohumeral muscular dystrophy.

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of the D4Z4 repeat on 4q35. We describe a FSHD family of unusual genetic complexity presenting with two independent mitotic contractions of D4Z4 in two successive generations. In addition, a non-pathogenic FSHD-sized allele of approximately the same size is interfering with the DNA diagnosis in this family. Interestingly, this allele is not recognized by the probes 4qA and 4qB representing two distal variants of 4qter, suggesting the presence of yet another, infrequent variant of 4qter.

Adult↗

PubMed2004

Mechanism and timing of mitotic rearrangements in the subtelomeric D4Z4 repeat involved in facioscapulohumeral muscular dystrophy.

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD1A) is associated with contractions of the polymorphic D4Z4 repeat on chromosome 4qter. Almost half of new FSHD mutations occur postfertilization, resulting in somatic mosaicism for D4Z4. Detailed D4Z4 analysis of 11 mosaic individuals with FSHD revealed a mosaic mixture of a contracted FSHD-sized allele and the unchanged ancestral allele in 8 cases, which is suggestive of a mitotic gene conversion without crossover. However, in 3 cases, the D4Z4 rearrangement resulted in two different-sized D4Z4 repeats, indicative of a gene conversion with crossover. In all cases, DNA markers proximal and distal to D4Z4 showed no allelic exchanges, suggesting that all rearrangements were intrachromosomal. We propose that D4Z4 rearrangements occur via a synthesis-dependent strand annealing model that relatively frequently allows for crossovers. Furthermore, the distribution of different cell populations in mosaic patients with FSHD suggests that mosaicism here results from D4Z4 rearrangements occurring during the first few zygotic cell divisions after fertilization.

Alleles↗

PubMed2004

Somatic mosaicism in FSHD often goes undetected.

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD1A) is associated with contractions of the polymorphic D4Z4 repeat array on chromosome 4qter. The disease has a high frequency of new mutations of mitotic origin. Pulsed-field gel electrophoresis-based studies show that mitotic mutations leading to somatic mosaicism occur equally frequently in patients and parents. Nevertheless, somatic mosaicism in FSHD is mainly reported in asymptomatic parents by applying standard Southern analysis after linear gel electrophoresis. Explaining this apparent discrepancy, we here demonstrate that somatic mosaicism in FSHD patients goes largely undetected using the standard diagnostic technique, indicating that linear electrophoresis is unsuitable to identify mosaic patients. As a consequence, the phenotype of mosaic patient's offspring will be underestimated, whereas the recurrence risk in the symptomatic mosaic individuals will be overestimated. Moreover, somatic mosaicism may partly explain the observation of anticipation in de novo kindreds. Therefore, clinicians should always consider pulsed-field gel electrophoresis analysis in de novo FSHD families, in particular when the patient's phenotype is much milder than expected based on D4Z4 length proper.

Adult↗

PubMed2002

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

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.

Chromosomes, Human, Pair 4↗