Linkage mapping of a new syndromic form of X-linked mental retardation, MRXS7, associated with obesity

Ahmad, Wasim; Fusco, Maurizio De; Haque, Muhammad Faiyaz ul; Aridon, Paolo; Sarno, Tiziana; Sohail, Muhammad; Haque, Sayedul; Siddique, M.; Ballabio, Andrea; Franco, Brunella; Casari, Giorgio

doi:10.1038/sj.ejhg.5200376

Cited by 13 publications

(6 citation statements)

References 25 publications

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“…Several primary or nonspecific MRX disorders have also been linked to Xq12, for example MRXS6 [16], MRXS7 [17], MRX9 [18], MRX14 [19], MRX20 [20], MRX58 [21], and MRXSSD [22]. The causative genes in these MRX patients have not been identified [35] and our findings in this study and other converging evidence would suggest that it would be reasonable to search for mutations in PJA1 in this cohort of MRX patients.…”

Section: Discussionmentioning

confidence: 41%

“…In this study, we have identified a novel human RING-H2 finger gene, PJA1, and mapped it to human chromosome Xq12, where several X-linked mental retardation (MRX) disorders have been associated [16][17][18][19][20][21][22]. We have also demonstrated that PJA1 can interact with E2 ubiquitin-conjugating enzyme UbcH5B and that PJA1 can function as an E3 ubiquitin-ligase during the ubiquitination process.…”

Section: Introductionmentioning

confidence: 89%

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PJA1, Encoding a RING-H2 Finger Ubiquitin Ligase, Is a Novel Human X Chromosome Gene Abundantly Expressed in Brain

Yü¹,

Chen

Tagle

et al. 2002

Genomics

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RING-finger proteins contain cysteine-rich, zinc-binding domains and are involved in the formation of macromolecular scaffolds important for transcriptional repression and ubiquitination. In this study, we have identified a RING-H2 finger gene, PJA1 (for praja-1), from a human brain cDNA library and mapped it to human chromosome Xq12 between markers DXS983 and DXS1216, a region implicated in X-linked mental retardation (MRX). Northern blot analysis indicated a 2.7-kb transcript that was abundantly expressed in the brain, including regions of the cerebellum, cerebral cortex, medulla, occipital pole, frontal lobe, temporal lobe, and putamen. Amino acid sequence analysis of the 71-kDa protein PJA1 showed 52.3% identity to human PJA2 (for praja-2, also known as NEURODAP1/KIAA0438) and also a significant identity to its homologs in rat, mouse, and zebrafish. In vitro binding and immunoprecipitation assays demonstrated that both PJA1 and PJA2 are able to bind the ubiquitin-conjugating enzyme UbcH5B. Moreover, the ubiquitination assay indicated that PJA1 and PJA2 have an E2-dependent E3 ubiquitin ligase activity. Thus our findings demonstrate that PJA1 can be involved in protein ubiquitination in the brain and is a suitable candidate gene for MRX.

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Section: Discussionmentioning

confidence: 41%

Section: Introductionmentioning

confidence: 89%

PJA1, Encoding a RING-H2 Finger Ubiquitin Ligase, Is a Novel Human X Chromosome Gene Abundantly Expressed in Brain

Yü¹,

Chen

Tagle

et al. 2002

Genomics

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“…Linkage analysis established linkage to Xq26–27. Ahmad et al (33) described a Pakistani family in which 10 males showed mental retardation, obesity, hypogonadism, and tapering fingers. Maximum linkage was obtained with the marker DXS1106.…”

Section: Mendelian Disordersmentioning

confidence: 99%

The Human Obesity Gene Map: The 2000 Update

Pérusse¹,

Chagnon²,

Weisnagel³

et al. 2001

Obesity Research

101

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This report constitutes the seventh update of the human obesity gene map incorporating published results up to the end of October 2000. Evidence from the rodent and human obesity cases caused by single‐gene mutations, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci uncovered in human genome‐wide scans and in cross‐breeding experiments in various animal models, and association and linkage studies with candidate genes and other markers are reviewed. Forty‐seven human cases of obesity caused by single‐gene mutations in six different genes have been reported in the literature to date. Twenty‐four Mendelian disorders exhibiting obesity as one of their clinical manifestations have now been mapped. The number of different quantitative trait loci reported from animal models currently reaches 115. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 130 studies reporting positive associations with 48 candidate genes. Finally, 59 loci have been linked to obesity indicators in genomic scans and other linkage study designs. The obesity gene map reveals that putative loci affecting obesity‐related phenotypes can be found on all chromosomes except chromosome Y. A total of 54 new loci have been added to the map in the past 12 months and the number of genes, markers, and chromosomal regions that have been associated or linked with human obesity phenotypes is now above 250. Likewise, the number of negative studies, which are only partially reviewed here, is also on the rise.

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“…As BFLS and Shasi syndromes map to the same chromosomal region, the possibility that they represent allelic conditions is not excluded. Similarly, Ahmad et al (87) reported a large family with a phenotype similar to that of Wilson-Turner syndrome and linkage to the Xp11.3-q22 region, overlapping with that of Wilson-Turner syndrome. Other X-linked syndromes with similar manifestations have been described, but in the absence of linkage studies, it is difficult to relate them to those reviewed here (see, for example (94)).…”

Section: X-linked Conditionsmentioning

confidence: 84%

Fat chance: genetic syndromes with obesity

2004

Clinical Genetics

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Although obesity shows high heritability, we are aware of only a small number of genes that affect adipose mass in humans. Genetic syndromes with obesity represent unique opportunities to gain insight into the control of energy balance. The majority of obesity syndromes can be distinguished by the presence of mental retardation. We performed a systematic search of such syndromes and reviewed the literature with a focus on distinguishing clinical features, the characteristics of their obesity, and the underlying pathogenetic mechanisms. We predict that the study of these conditions will shed light on common forms of obesity.

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Linkage mapping of a new syndromic form of X-linked mental retardation, MRXS7, associated with obesity

Cited by 13 publications

References 25 publications

PJA1, Encoding a RING-H2 Finger Ubiquitin Ligase, Is a Novel Human X Chromosome Gene Abundantly Expressed in Brain

PJA1, Encoding a RING-H2 Finger Ubiquitin Ligase, Is a Novel Human X Chromosome Gene Abundantly Expressed in Brain

The Human Obesity Gene Map: The 2000 Update

Fat chance: genetic syndromes with obesity

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