Stocco dos Santos X‐linked mental retardation syndrome: Clinical elucidation and localization to Xp11.3–Xq21.3

Stocco, Rita de Cássia; Castro, Nelson H.C.; Holmes, Anthony; Beçak, Willy; Tackels-Horne, Darci; Lindsey, Charles Julian; Lubs, Herbert A.; Stevenson, Roger E.; Schwartz, Charles E.

doi:10.1002/ajmg.a.20021

Cited by 14 publications

(14 citation statements)

References 9 publications

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“…These findings suggest that disruption of hKIAA1202 is causative for the shared clinical features, which include mental delay. Moreover, we identified a c.1422A>G exchange, not detected in 1,266 control X-chromosomes, segregating in a small family, and a c.3266C>T transition, not found in 1,021 control X-chromosomes, which segregates with the Stocco dos Santos XLMR syndrome in a large fourgeneration family (Stocco dos Santos et al 2003). Finally, we have shown that hKIAA1202 and its mouse homologue mKiaa1202 are expressed in adult and foetal brain.…”

Section: Discussionmentioning

confidence: 70%

“…Their mothers also have experienced seizures and periods of depression. Although XCI studies in peripheral blood of all obligate carriers showed skewed inactivation in excess of 90:10 (Stocco dos Santos et al 2003), it is possible that a remaining small amount of mutant protein exerts its influence in a dominant negative way, leading to their moderate phenotype. Alternatively, the XCI pattern at the hKIAA1202 locus may be variable during development or could be tissue specific (Sheardown et al 1996).…”

Section: Genomic Organisation Of Hkiaa1202mentioning

confidence: 99%

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Disruptions of the novel KIAA1202 gene are associated with X-linked mental retardation

et al. 2005

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The extensive heterogeneity underlying the genetic component of mental retardation (MR) is the main cause for our limited understanding of the aetiology of this highly prevalent condition. Hence we set out to identify genes involved in MR. We investigated the breakpoints of two balanced X;autosome translocations in two unrelated female patients with mild/moderate MR and found that the Xp11.2 breakpoints disrupt the novel human KIAA1202 (hKIAA1202) gene in both cases. We also identified a missense exchange in this gene, segregating with the Stocco dos Santos XLMR syndrome in a large four-generation pedigree but absent in >1,000 control X-chromosomes. Among other phenotypic characteristics, the affected males in this family present with severe MR, delayed or no speech, seizures and hyperactivity. Molecular studies of hKIAA1202 determined its genomic organisation, its expression throughout the brain and the regulation of expression of its mouse homologue during development. Transient expression of the wild-type KIAA1202 protein in HeLa cells showed partial colocalisation with the F-actin based cytoskeleton. On the basis of its domain structure, we argue that hKIAA1202 is a new member of the APX/Shroom protein family. Members of this family contain a PDZ and two ASD domains of unknown function and have been shown to localise at the cytoskeleton, and play a role in neurulation, cellular architecture, actin remodelling and ion channel function. Our results suggest that hKIAA1202 may be important in cognitive function and/or development.

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Section: Discussionmentioning

confidence: 70%

Section: Genomic Organisation Of Hkiaa1202mentioning

confidence: 99%

Disruptions of the novel KIAA1202 gene are associated with X-linked mental retardation

et al. 2005

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“…The SYP gene is the strongest candidate for the seizures observed in these patients as loss or mutations in this gene have been associated with seizures [Tarpey et al, 2009]. Seizures are also a feature of Stocco dos Santos syndrome [Stocco dos Santos et al, 2003], which is caused by mutations in the SHROOM4 (OMIM*300579) gene (∼50.4 Mb, Fig. 3) [Hagens et al, 2006].…”

Section: Discussionmentioning

confidence: 99%

A de novo duplication of Xp11.22–p11.4 in a girl with intellectual disability, structural brain anomalies, and preferential inactivation of the normal X chromosome

Holden

Clarkson

Thomas

et al. 2010

American J of Med Genetics Pt A

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Only a small number of individuals with duplications within the proximal short arm of the X chromosome have been reported. The majority of patients have duplications encompassing Xp11-p21, or extend more distally into Xp22. We report on a female patient who presented within the first year of life with plagiocephaly, speech delay, and epilepsy. Brain MRI showed a relatively thin cerebral cortex, abnormal periventricular white matter, and abnormal vessels in the left inferior parietal region. Cytogenetic and microsatellite analysis of the patient and her parents showed that she has a de novo duplication of Xp11.22-Xp11.4 on her paternal X chromosome. FISH analysis using fluorescently labeled BACs followed by array analysis including an X tilepath BAC array showed that a 12.3 Mb interval between 40.4 Mb and 52.7 Mb from the Xp telomere (NCBI build 36) was duplicated and excluded the presence of additional rearrangements along the X chromosome. Interestingly, X-inactivation studies in peripheral blood leukocytes showed that the duplicated (paternal) X chromosome was active in the majority of cells, in contrast to other patients with Xp duplications in whom X inactivation is random or skewed toward the normal X. These findings suggest that overexpression of genes from proximal Xp is likely to have contributed to her clinical phenotype.

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“…In addition to the PQBP1 gene, multiple other genes are duplicated within this 4.7 Mb region and may contribute to our patient's phenotype. Mutations in the SHROOM4 gene have been linked to Stocco dos Santos X‐linked mental retardation syndrome, which is characterized by severe intellectual disability, bilateral congenital hip dislocation, and short stature [Stocco dos Santos et al, 2003]. Mutations in the FTSJ1 gene are a cause of non‐syndromic X‐linked moderate–severe intellectual disability [Froyen et al, 2007].…”

Section: Discussionmentioning

confidence: 99%

Whole gene duplication of the PQBP1 gene in syndrome resembling Renpenning

Flynn

Zou

Milunsky

2010

American J of Med Genetics Pt A

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Renpenning syndrome is a well-described X-linked condition associated with multiple congenital anomalies and intellectual disability [OMIM 309500]. Typical signs include microcephaly, dysmorphic features, short stature, small testes, and lean body build. Renpenning syndrome is caused by mutations in the polyglutamine binding protein 1 (PQBP1) gene. Missense mutations, insertions, deletions, and duplications within the gene have been well-described. We present a 47-year-old male with clinical features resembling Renpenning syndrome. He has moderate intellectual disability, seizures since infancy, short stature, small testes, and dysmorphic features. Of note, our patient is normocephalic. A CT scan at 14 years of age showed cerebral atrophy. He had previously been verbally communicative and had few behavioral issues. Recently, our patient has regressed and has become uncommunicative, displaying little and unclear speech. He now exhibits memory and recognition loss and is uncooperative, aggressive, self-abusive, and incontinent. The reason for his regression within the past 4 years is unclear. SNP microarray analysis (500K) revealed a 4.7 Mb duplication at Xp11.22-p11.23. Multiple ligation probe amplification (MLPA) of the PQBP1 gene contained within this duplicated region confirmed a duplication of the entire PQBP1 gene. Multiple other genes are duplicated within this 4.7 Mb region and may contribute to his phenotype.

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Stocco dos Santos X‐linked mental retardation syndrome: Clinical elucidation and localization to Xp11.3–Xq21.3

Cited by 14 publications

References 9 publications

Disruptions of the novel KIAA1202 gene are associated with X-linked mental retardation

Disruptions of the novel KIAA1202 gene are associated with X-linked mental retardation

A de novo duplication of Xp11.22–p11.4 in a girl with intellectual disability, structural brain anomalies, and preferential inactivation of the normal X chromosome

Whole gene duplication of the PQBP1 gene in syndrome resembling Renpenning

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