Digital Repository for Department of Preventive Medicine

Background: Patellar luxation (PL) is a common orthopedic affection among farm and pet animals with mostly congenital (environmental and/or genetic) background. Aim: We report here the first observation of lateral PL in Hejazi goats bred in Libya. Methods: Five Hejazi goats aged between 4 months and 2 years with severe hind limb lameness were admitted to Al-Sorouh veterinary clinic in Tripoli during the period from 2016 to 2018. The goats were thoroughly examined clinically and radiographically. Two goats were surgically treated, and the other three cases were not because of either the cost limitation or expected poor prognosis. The surgical intervention involved femoral trochlear sulcoplasty, medial joint capsule imbrication, and tibial tuberosity transposition. Results: The clinical examination showed grade III–IV lateral PL. Radiologically, there were unilateral or bilateral, ventrocaudal, and dorsal PLs. Two cases were referred to surgical correction. One case almost restored the normal movement of stifle joint together with a good general status 1 year postsurgery. However, the surgical treatment was not effective in correcting the luxated patella in the second case. Conclusion: Lateral PL is common among orthopedic affections in Hejazi goats in Libya, and its surgical treatment provided a quite convenient approach. An association between inbreeding and the PL was suggested in those cases. Keywords: Clinical and radiological findings, Hejazi goat breed, Inbreeding, Patellar luxation, Surgical treatment.
Mohamed Hamrouni S. Abushhiwa, Abdulrhman Mohamed Salah Alrtib, Taher N. Elmeshreghi, Mouna Abdunnabi Abdunnabi Abdunnabi, Mansur Ennuri Moftah Shmela, Emad M R Bennour(3-2021)

Background: Patellar luxation (PL) is a common orthopedic affection among farm and pet animals with mostly congenital (environmental and/or genetic) background. Aim: We report here the first observation of lateral PL in Hejazi goats bred in Libya. Methods: Five Hejazi goats aged between 4 months and 2 years with severe hind limb lameness were admitted to Al-Sorouh veterinary clinic in Tripoli during the period from 2016 to 2018. The goats were thoroughly examined clinically and radiographically. Two goats were surgically treated, and the other three cases were not because of either the cost limitation or expected poor prognosis. The surgical intervention involved femoral trochlear sulcoplasty, medial joint capsule imbrication, and tibial tuberosity transposition. Results: The clinical examination showed grade III–IV lateral PL. Radiologically, there were unilateral or bilateral, ventrocaudal, and dorsal PLs. Two cases were referred to surgical correction. One case almost restored the normal movement of stifle joint together with a good general status 1 year postsurgery. However, the surgical treatment was not effective in correcting the luxated patella in the second case. Conclusion: Lateral PL is common among orthopedic affections in Hejazi goats in Libya, and its surgical treatment provided a quite convenient approach. An association between inbreeding and the PL was suggested in those cases. arabic 4 English 29
Taher N. Elmeshreghi, Mansur Ennuri Moftah Shmela, Mouna Abdunnabi Abdunnabi Abdunnabi, Emad M R Bennour(6-2021)

The human 11p15 region is divided into two independent imprinted domains, the H19/IGF2 and CDKN1C/KCNQ1 domains. Each domain is regulated by its own imprinting control regions, ICR1 and ICR2, which carry opposite germline imprints. The expression of 11p15 imprinted genes is regulated by two major mechanisms. ICR1 binds a zinc finger protein (CTCF) on the unmethylated maternal allele and acts as a chromatin insulator, whereas ICR2 is unmethylated on the paternal allele and serves as a promoter for a regulatory non-coding RNA (KCNQ1OT1). Dysregulation of 11p15 genomic imprinting results in two human foetal growth disorders: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes, which display opposite growth phenotypes. Various 11p15 epigenetic and genetic defects result in BWS and SRS. Gain or loss of DNA methylation account for 60% of BWS and SRS and, in most cases, the mechanism of the DNA methylation defect is unknown. The overall aim of this thesis was to decipher the mechanisms resulting in loss or gain of DNA methylation at ICR1 or ICR2 by investigating large cohorts of BWS and SRS patients displaying a “primary” DNA methylation defect. We aimed at establishing what was the incidence of copy number variations (CNVs) (duplications, deletions and segmental uniparental isodisomies) confined to one or one part of the H19/IGF2 or CDKN1C/KCNQ1 domains. We also screened extensively the ICR1 imprinting control region in BWS and SRS patients to identify new genetic defects. We show in this work that genetic defects in cis account for a significant proportion (approximately 30%) of BWS patients with ICR1 gain of DNA methylation but are rare in SRS and BWS patients with loss of DNA methylation at ICR1 and ICR2, respectively. We describe novel small gain and loss CNVs involving only part of the two domains in BWS and SRS. We also describe, for the first time, mutations and small deletions involving binding sites for the OCT4 and SOX2 pluripotency factors. Those defects account for approximately 14% of BWS cases and result in a BWS phenotype upon maternal transmission. We further characterize the role of OCT4/SOX2 pluripotency factors in the maintenance of genomic imprinting at the H19/IGF2 domain in mouse embryonic stem cells. By screening the whole 11p15 region for susceptibility alleles for loss or gain of DNA methylation, our group identified a novel 4.5 kb cis-regulatory region within the CDKN1C/KCNQ1 domain. A specific 4.5 kb haplotype confers, upon maternal transmission, a risk of ICR2 loss of DNA methylation in BWS patients. This study investigated the mechanism involved in the risk of ICR2 loss of DNA methylation in BWS and showed that within this 4.5 kb region, two SNPs (rs11823023 and rs179436) affect CTCF occupancy at DNA motifs flanking the CTCF 20 bp core motifs. This study identifies a new cis-regulatory region and highlights the crucial role of CTCF for the regulation of genomic imprinting at the CDKN1C/KCNQ1 domain. These recent findings bring new insights in the regulation of genomic imprinting at both the IGF2/H19 and CDKN1C/KCNQ1 domains. arabic 8 English 50
Mansur Ennuri Moftah Shmela(9-2014)

The imprinted expression of the IGF2 and H19 genes is controlled by the imprinting control region 1 (ICR1) located at chromosome 11p15.5. This methylation-sensitive chromatin insulator works by binding the zincfinger protein CTCF in a parent-specific manner. DNA methylation defects involving the ICR1 H19/IGF2 domain result in two growth disorders with opposite phenotypes: an overgrowth disorder, the Beckwith– Wiedemann syndrome (maternal ICR1 gain of methylation in 10% of BWS cases) and a growth retardation disorder, the Silver–Russell syndrome (paternal ICR1 loss of methylation in 60% of SRS cases). Although a few deletions removing part of ICR1 have been described in some familial BWS cases, little information is available regarding the mechanism of ICR1 DNA methylation defects. We investigated the CTCF gene and the ICR1 domain in 21 BWS patients with ICR1 gain of methylation and 16 SRS patients with ICR1 loss of methylation. We identified four constitutional ICR1 genetic defects in BWS patients, including a familial case. Three of those defects are newly identified imprinting defects consisting of small deletions and a single mutation, which do not involve one of the CTCF binding sites. Moreover, two of those defects affect OCT-binding sequences which are suggested to maintain the unmethylated state of the maternal allele. A single-nucleotide variation was identified in a SRS patient. Our data extends the spectrum of constitutive genetic ICR1 abnormalities and suggests that extensive and accurate analysis of ICR1 is required for appropriate genetic counseling in BWS patients with ICR1 gain of methylation.
Demars, J., Mansur Ennuri Moftah Shmela, S. Rossignol, J. Okabe, I. Netchine, S. Azzi, S. Cabrol, C. Le Caignec, A. David , Y. Le Bouc, A. El-Osta , C. Gicquel(9-2010)

The imprinted 11p15 region is organized in two domains, each of them under the control of its own imprinting control region (ICR1 for the IGF2/H19 domain and ICR2 for the KCNQ1OT1/CDKN1C domain). Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes. Various 11p15 genetic and epigenetic defects have been demonstrated in BWS and SRS. Among them, isolated DNA methylation defects account for approximately 60% of patients. To investigate whether cryptic copy number variations (CNVs) involving only part of one of the two imprinted domains account for 11p15 isolated DNA methylation defects, we designed a single nucleotide polymorphism array covering the whole 11p15 imprinted region and genotyped 185 SRS or BWS cases with loss or gain of DNA methylation at either ICR1 or ICR2. We describe herein novel small gain and loss CNVs in six BWS or SRS patients, including maternally inherited cis-duplications involving only part of one of the two imprinted domains. We also show that ICR2 deletions do not account for BWS with ICR2 loss of methylation and that uniparental isodisomy involving only one of the two imprinted domains is not a mechanism for SRS or BWS. arabic 22 English 137
- Demars, J., S. Rossignol, I. Netchine, K. S. Lee, Mansur Ennuri Moftah Shmela, L. Faivre, J. Weill, S. Odent, S. Azzi, P. Callier, J. Lucas, C. Dubourg, J. Andrieux, Y. Le Bouc, A. El-Osta , C. Gicquel(10-2011)

La croissance fœtale est un processus complexe dépendant de facteurs génétiques, environnementaux, nutritionnels et hormonaux d’origine maternelle, placentaire et fœtale. Le système IGF est l’un des systèmes hormonaux les plus importants pour la régulation de la croissance fœtale et placentaire [1]. Le gène IGF-II est régulé par le phénomène d’empreinte parentale et est exprimé seulement à partir de l’allèle paternel dans la majorité des tissus pendant la vie fœtale. Les gènes soumis à empreinte parentale sont régulés de manière spécifique et sont particulièrement vulnérables aux signaux environnementaux et nutritionnels. La dérégulation d’un groupe de gènes de la région 11p15 soumise à empreinte parentale, incluant le gène IGF-II, est responsable de deux pathologies de croissance fœtale (les syndromes de Silver-Russell, OMIM 180860 et de Wiedemann-Beckwith, OMIM 130650) qui ont une présentation phénotypique opposée. Ces deux syndromes représentent d’excellents modèles de pathologies humaines pour l’étude de la régulation de l’empreinte parentale. arabic 9 English 26
- Demars, J , S. Rossignol, Mansur Ennuri Moftah Shmela, I. Netchine, S. Azzi, A. El-Osta, Y. Le Bouc, C. Gicquel(1-2012)

The imprinted expression of the IGF2 and H19 genes is controlled by the imprinting control region 1 (ICR1) located at chromosome 11p15.5. DNA methylation defects involving ICR1 result in two growth disorders with opposite phenotypes: an overgrowth disorder, the Beckwith-Wiedemann syndrome (maternal ICR1 hypermethylation in 10% of BWS cases) and a growth retardation disorder, the Silver-Russell syndrome (paternal ICR1 loss of methylation in 60% of SRS cases). In familial BWS, hypermethylation of ICR1 has been found in association with microdeletion of repetitive DNA motifs within ICR1 that bind the zinc finger protein CTCF; but more recently, ICR1 point mutations were described in BWS pedigrees. We present a case report of two brothers with BWS and prolonged post-pubertal growth resulting in very large stature. A maternally inherited point mutation was identified in ICR1 in both brothers, which altered binding of OCT transcription factors. The same mutation was present on the paternally inherited allele of their unaffected mother. This is a second report of a point mutation causing ICR1 hypermethylation by altering an OCT-binding motif. The atypical growth phenotype of the brothers may be connected to the unusual underlying cause of their BWS. arabic 24 English 118
Rebecca L Poole, Donald J Leith, Louise E Docherty, Mansur Ennuri Moftah Shmela, Christine Gicquel,, Miranda Splitt, I Karen Temple, Deborah J G Mackay(2-2012)

The 11p15 region is organised into two independent imprinted domains controlled by imprinting control regions, which carry opposite germline imprints. Dysregulation of 11p15 genomic imprinting results in two human fetal growth disorders (Silver-Russell syndrome (SRS, MIM 180860) and Beckwith-Wiedemann syndrome (BWS, MIM 130650)) with opposite growth phenotypes. The mouse orthologous region on distal chromosome 7 (dist7) is well conserved in its organisation and its regulation. Targeted mutagenesis in mice has provided highly valuable clues in terms of the mechanisms involved in the regulation of genomic imprinting of the 11p15/dist7 imprinted region. On the other hand, the recent identification of unexpected genetic defects in BWS and SRS patients also brought new insights into the mechanisms of 11p15 imprinting regulation. However, some mouse models and human genetic defects show contradictions in term of growth phenotypes and parental transmission. In this review, we extensively analyse those various mouse and human models and more particularly models with mutations affecting the two imprinting centres, in order to improve our understanding of regulation of 11p15/dist7 genomic imprinting. arabic 21 English 117
Mansur Ennuri Moftah Shmela, C. F. Gicquel(1-2013)