Schwartz, C. et al. The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. J. Med. Genet. 44, 472-477

Journal of Medical Genetics (Impact Factor: 6.34). 08/2007; 44(7):472-7. DOI: 10.1136/jmg.2006.048637
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A novel missense mutation in the mediator of RNA polymerase II transcription subunit 12 (MED12) gene has been found in the original family with Lujan syndrome and in a second family (K9359) that was initially considered to have Opitz-Kaveggia (FG) syndrome. A different missense mutation in the MED12 gene has been reported previously in the original family with FG syndrome and in five other families with compatible clinical findings. Neither sequence alteration has been found in over 1400 control X chromosomes. Lujan (Lujan-Fryns) syndrome is characterised by tall stature with asthenic habitus, macrocephaly, a tall narrow face, maxillary hypoplasia, a high narrow palate with dental crowding, a small or receding chin, long hands with hyperextensible digits, hypernasal speech, hypotonia, mild-to-moderate mental retardation, behavioural aberrations and dysgenesis of the corpus callosum. Although Lujan syndrome has not been previously considered to be in the differential diagnosis of FG syndrome, there are some overlapping clinical manifestations. Specifically, these are dysgenesis of the corpus callosum, macrocephaly/relative macrocephaly, a tall forehead, hypotonia, mental retardation and behavioural disturbances. Thus, it seems that these two X-linked mental retardation syndromes are allelic, with mutations in the MED12 gene.

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Available from: Alain Verloes, Oct 09, 2014
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    • "The original family with Luhan syndrome [Lujan et al., 1984] is also known as Luhan–Fryns syndrome with XLID with Marfanoid features. This family and a second unrelated family were found to have a different sequence alteration (c.3020A>G, p.N1007S) in exon 22 of the MED12 gene [Schwartz et al., 2007]. This observation means FG syndrome and Lujan syndrome are allelic, with different mutations in the MED12 gene. "
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    ABSTRACT: MED12: is a member of the large Mediator complex, which has a critical and central role in RNA polymerase II transcription. As a multiprotien complex, Mediator regulates signals involved in cell growth, development, and differentiation, and it is involved in a protein network required for extraneuronal gene silencing and also functions as a direct suppressor of Gli3-dependent Sonic hedgehog signaling. This may explain its role in several different X-linked intellectual disability syndromes that share some overlapping clinical features. This review will compare and contrast four different clinical conditions that have been associated with different mutations in MED12, which is located at Xq13. To date, these conditions include Opitz-Kaveggia (FG) syndrome, Lujan syndrome, Ohdo syndrome (Maat-Kievit-Brunner type, or OSMKB), and one large family with profound X-linked intellectual disability due to a novel c.5898insC frameshift mutation that unlike the other three syndromes, resulted in affected female carriers and truncation of the MED12 protein. It is likely that more MED12 mutations will be detected in sporadic patients and X-linked families with intellectual disability and dysmorphic features as exome sequencing becomes more commonly utilized, and this overview of MED12-related disorders may help to correlate MED12 genotypes with clinical findings. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 10/2013; 161(11). DOI:10.1002/ajmg.a.36183 · 2.16 Impact Factor
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    • "Lujan–Fryns or X-linked mental retardation syndrome (OMIM #309520) is characterized by moderate to mild mental retardation, distinct facial dysmorphism (prominent forehead, maxillary hypoplasia , small mandible, long nose with short and deep philtrum, thin upper lip, and low-set normally shaped ears), hypernasal voice, marfanoid-like features (tall stature after puberty and long, thin hyper-extensible fingers and toes), hypotonia [Lujan et al., 1984; Fryns and Buttiens, 1987] and agenesis/dysgenesis of the corpus callosum. The syndrome is caused by a mutation in the MED12 gene on Xq13 [Schwartz et al., 2007]. Behavioral problems and psychiatric disorders are often present in Lujan–Fryns patients, whereas " autistic-like disorders " , in specific, have been described in 62.5% of all cases reported up to now in literature. "
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    ABSTRACT: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disabilities with various etiologies, but with a heritability estimate of more than 90%. Although the strong correlation between autism and genetic factors has been long established, the exact genetic background of ASD remains unclear. A number of genetic syndromes manifest ASD at higher than expected frequencies compared to the general population. These syndromes account for more than 10% of all ASD cases and include tuberous sclerosis, fragile X, Down, neurofibromatosis, Angelman, Prader-Willi, Williams, Duchenne, etc. Clinicians are increasingly required to recognize genetic disorders in individuals with ASD, in terms of providing proper care and prognosis to the patient, as well as genetic counseling to the family. Vice versa, it is equally essential to identify ASD in patients with genetic syndromes, in order to ensure correct management and appropriate educational placement. During investigation of genetic syndromes, a number of issues emerge: impact of intellectual disability in ASD diagnoses, identification of autistic subphenotypes and differences from idiopathic autism, validity of assessment tools designed for idiopathic autism, possible mechanisms for the association with ASD, etc. Findings from the study of genetic syndromes are incorporated into the ongoing research on autism etiology and pathogenesis; different syndromes converge upon common biological backgrounds (such as disrupted molecular pathways and brain circuitries), which probably account for their comorbidity with autism. This review paper critically examines the prevalence and characteristics of the main genetic syndromes, as well as the possible mechanisms for their association with ASD. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2013; 162(4). DOI:10.1002/ajmg.b.32152 · 3.42 Impact Factor
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    • "Mutations in the genes encoding mediator, cohesin and the cohesin loading factor Nipbl can cause an array of human developmental syndromes and diseases. Mediator mutations have been associated with Opitz-Kaveggia (FG) syndrome, Lujan syndrome, schizophrenia, Transposition of the Great Arteries (TGA) syndrome and colon cancer progression (Ding et al., 2008; Firestein et al., 2008; Muncke et al., 2003; Philibert and Madan, 2007; Risheg et al., 2007; Schwartz et al., 2007). Mutations in Nipbl and cohesin are responsible for most cases of Cornelia de Lange syndrome, which is characterized by developmental defects and mental retardation and appears to be the result of mis-regulation of gene expression rather than chromosome cohesion or mitotic abnormalities (Krantz et al., 2004; Strachan, 2005; Tonkin et al., 2004). "
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    ABSTRACT: Embryonic stem cells and induced pluripotent stem cells hold great promise for regenerative medicine. These cells can be propagated in culture in an undifferentiated state but can be induced to differentiate into specialized cell types. Moreover, these cells provide a powerful model system for studies of cellular identity and early mammalian development. Recent studies have provided insights into the transcriptional control of embryonic stem cell state, including the regulatory circuitry underlying pluripotency. These studies have, as a consequence, uncovered fundamental mechanisms that control mammalian gene expression, connect gene expression to chromosome structure, and contribute to human disease.
    Cell 03/2011; 144(6):940-54. DOI:10.1016/j.cell.2011.01.032 · 32.24 Impact Factor
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