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Biomedical subjects

Roger E Stevenson

Publications and source records attributed to Roger E Stevenson.

At least 19 recordsLinked to original sources
PubMed2006

Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28.

OBJECTIVE: Our goal was to describe the neurologic and clinical features of affected males from families with X-linked patterns of severe mental retardation, hypotonia, recurrent respiratory infection, and microduplication of Xq28 that consistently includes the MECP2 (methyl-CpG binding protein 2) gene. STUDY DESIGN: To identify duplications, multiplex ligation-dependent probe amplification of the MECP2 gene was performed on male probands from families with X-linked mental retardation. The males either had linkage to Xq28 or had a phenotype consistent with previous reports involving Xq28 functional disomy. After detection of a duplication of MECP2, additional family members were tested to confirm the MECP2 duplication segregated with the affected phenotype, and X-inactivation studies were performed on carrier females. RESULTS: Six families with multiple affected males having MECP2 duplications were identified by multiplex ligation-dependent probe amplification, and the carrier mothers were subsequently shown to have highly skewed X inactivation. In 5 of 6 families, the microduplication extended proximally to include the L1 cell adhesion molecule gene. The primary clinical features associated with this microduplication are infantile hypotonia, recurrent respiratory infection, severe mental retardation, absence of speech development, seizures, and spasticity. CONCLUSIONS: Although many of the phenotypic features of our patients are rather nonspecific in cohorts of individuals with syndromic and nonsyndromic mental retardation, the proneness to infection is quite striking because the patients had normal growth and were not physically debilitated. Although the etiology of the infections is not understood, we recommend considering MECP2 dosage studies and a genetics referral in individuals with severe developmental delay and neurologic findings, especially when a history of recurrent respiratory ailments has been documented.

Adolescent↗
PubMed2006

Mutations in the gene encoding the Sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X-linked mental retardation.

In a systematic sequencing screen of the coding exons of the X chromosome in 250 families with X-linked mental retardation (XLMR), we identified two nonsense mutations and one consensus splice-site mutation in the AP1S2 gene on Xp22 in three families. Affected individuals in these families showed mild-to-profound mental retardation. Other features included hypotonia early in life and delay in walking. AP1S2 encodes an adaptin protein that constitutes part of the adaptor protein complex found at the cytoplasmic face of coated vesicles located at the Golgi complex. The complex mediates the recruitment of clathrin to the vesicle membrane. Aberrant endocytic processing through disruption of adaptor protein complexes is likely to result from the AP1S2 mutations identified in the three XLMR-affected families, and such defects may plausibly cause abnormal synaptic development and function. AP1S2 is the first reported XLMR gene that encodes a protein directly involved in the assembly of endocytic vesicles.

Adaptor Protein Complex sigma Subunits↗
PubMed2006

X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology.

Mutations in the creatine transporter gene, SLC6A8 (MIM 30036), located in Xq28, have been found in families with X-linked mental retardation (XLMR) as well as in males with idiopathic mental retardation (MR). In order to estimate the frequency of such mutations in the MR population, a screening of 478 males with MR of unknown cause was undertaken. All 13 exons of SLC6A8 were sequenced using genomic DNA. Six novel potentially pathogenic mutations were identified that were not encountered in at least 588 male control chromosomes: two deletions (p.Asn336del, p.Ile347del) and a splice site alteration (c.1016+2C>T) are considered pathogenic based on the nature of the variant. A mutation (p.Arg391Trp) should be considered pathogenic owing to its localization in a highly conserved region. Two other missense variants (p.Lys4Arg, p.Gly26Arg) are not conserved but were not observed in over 300 male control chromosomes. Their pathogenicity is uncertain. A missense variant (p.Val182Met), was classified as a polymorphism based on a normal creatine/creatinine (Cr:Crn) ratio and cerebral creatine signal in proton magnetic resonance spectroscopy (H-MRS) in the patient. Furthermore, we found 14 novel intronic and neutral variants that were not encountered in at least 280 male control chromosomes and should be considered as unclassified variants. Our findings of a minimum of four pathogenic mutations and two potentially pathogenic mutations indicate that about 1% of males with MR of unknown etiology might have a SLC6A8 mutation. Thus, DNA sequence analysis and/or a Cr:Crn urine screen is warranted in any male with MR of unknown cause.

Amino Acid Sequence↗
PubMed2006

A microdeletion in Xp11.3 accounts for co-segregation of retinitis pigmentosa and mental retardation in a large kindred.

In a previous report, Aldred et al. [1994] described a 5-generation family in which severe retinitis pigmentosa (RP) co-segregates with mild-moderate mental retardation as an X-linked recessive phenotype mapping to the broad interval between Xp21-q21. We re-examined this family, initially analyzing RP2, a gene in the disease interval that was identified as a cause of RP after the initial report of this family. We found that the male propositus lacked the 5' three exons of RP2 and that RP2 marks the centromeric boundary of a 1.27 Mb deletion that includes two other annotated genes (SLC9A7, CHST7), one predicted transcript encoding a zinc finger protein (FLJ20344) and two highly conserved miRNAs (mir221, mir222). We conclude that this family is segregating a contiguous gene deletion and that the absence of a functional RP2 accounts, at least in part, for the retinal degeneration while deletion of one or more of the other genes is likely responsible for the mental retardation phenotype.

Antiporters↗
PubMed2005

Array-based comparative genomic hybridization analysis of recurrent chromosome 15q rearrangements.

Genomic rearrangements of chromosome 15q11-q13 cause diverse phenotypes including autism, Prader-Willi syndrome (PWS), and Angelman syndrome (AS). This region is subject to genomic imprinting and characterized by complex combinations of low copy repeat elements. Prader-Willi and Angelman syndrome are caused primarily by 15q11-13 deletions of paternal and maternal origin, respectively. Autism is seen with maternal, but not paternal, interstitial duplications. Isodicentric 15q, most often of maternal origin, is associated with a complex phenotype often including autistic features. Limitations of conventional cytogenetic tests preclude a detailed analysis in most patients with 15q rearrangements. We have developed a microarray for comparative genomic hybridization utilizing 106 genomic clones from chromosome 15q to characterize this region. The array accurately localized all breakpoints associated with gains or losses on 15q. The results confirmed the location of the common breakpoints associated with interstitial deletions and duplications. The majority of idic(15q) chromosomes are comprised of symmetrical arms with four copies of the breakpoint 1 to breakpoint 5 region. Patients with less common breakpoints that are not distinguished by routine cytogenetic methods were more accurately characterized by array analysis. This microarray provides a detailed characterization for chromosomal abnormalities involving 15q11-q14 and is useful for more precise genotype-phenotype correlations for autism, PWS, AS, and idic(15) syndrome.

Chromosome Aberrations↗
PubMed2005

Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene.

Allan-Herndon-Dudley syndrome was among the first of the X-linked mental retardation syndromes to be described (in 1944) and among the first to be regionally mapped on the X chromosome (in 1990). Six large families with the syndrome have been identified, and linkage studies have placed the gene locus in Xq13.2. Mutations in the monocarboxylate transporter 8 gene (MCT8) have been found in each of the six families. One essential function of the protein encoded by this gene appears to be the transport of triiodothyronine into neurons. Abnormal transporter function is reflected in elevated free triiodothyronine and lowered free thyroxine levels in the blood. Infancy and childhood in the Allan-Herndon-Dudley syndrome are marked by hypotonia, weakness, reduced muscle mass, and delay of developmental milestones. Facial manifestations are not distinctive, but the face tends to be elongated with bifrontal narrowing, and the ears are often simply formed or cupped. Some patients have myopathic facies. Generalized weakness is manifested by excessive drooling, forward positioning of the head and neck, failure to ambulate independently, or ataxia in those who do ambulate. Speech is dysarthric or absent altogether. Hypotonia gives way in adult life to spasticity. The hands exhibit dystonic and athetoid posturing and fisting. Cognitive development is severely impaired. No major malformations occur, intrauterine growth is not impaired, and head circumference and genital development are usually normal. Behavior tends to be passive, with little evidence of aggressive or disruptive behavior. Although clinical signs of thyroid dysfunction are usually absent in affected males, the disturbances in blood levels of thyroid hormones suggest the possibility of systematic detection through screening of high-risk populations.

Adolescent↗
PubMed2005

Renpenning syndrome comes into focus.

Renpenning syndrome represents a prototypic X-linked mental retardation condition with full expression of the phenotype in males and little or no expression in females. The predominant clinical findings are microcephaly, long narrow face, short stature with lean body build, and small testes. Mental retardation, usually of severe degree, occurs in 95% of cases. Less than 20% of cases have major malformations, the most common being cardiac defects and cleft palate. Subsequent to the description of mutations in the polyglutamine tract binding protein 1 (PQBP1) in Sutherland-Haan syndrome, Hamel cerebropalatocardiac syndrome, MRX55, and two small XLMR families, a single nucleotide insertion has been found in the original family with Renpenning syndrome and an AGAG deletion in a second family with the Renpenning syndrome. Mutations have also been found in Golabi-Ito-Hall syndrome, Porteous syndrome, and an additional small family. It is now demonstrated that five named XLMR syndromes (Sutherland-Haan, Hamel cerebropalatocardiac, Golabi-Ito-Hall, Porteous, and Renpenning), one nonsyndromic family (MRX55), and three small XLMR families have PQBP1 mutations and are thus allelic XLMR entities. In acknowledgement of the historical importance of the original report of Renpenning syndrome [1962], we propose that the entities with PQBP1 mutations be combined under the name of Renpenning syndrome.

Abnormalities, Multiple↗
PubMed2005

XLMR in MRX families 29, 32, 33 and 38 results from the dup24 mutation in the ARX (Aristaless related homeobox) gene.

BACKGROUND: X-linked mental retardation (XLMR) is the leading cause of mental retardation in males. Mutations in the ARX gene in Xp22.1 have been found in numerous families with both nonsyndromic and syndromic XLMR. The most frequent mutation in this gene is a 24 bp duplication in exon 2. Based on this fact, a panel of XLMR families linked to Xp22 was tested for this particular ARX mutation. METHODS: Genomic DNA from XLMR families linked to Xp22.1 was amplified for exon 2 in ARX using a Cy5 labeled primer pair. The resulting amplicons were sized using the ALFexpress automated sequencer. RESULTS: A panel of 11 families with X-linked mental retardation was screened for the ARX 24dup mutation. Four nonsyndromic XLMR families - MRX29, MRX32, MRX33 and MRX38 - were found to have this particular gene mutation. CONCLUSION: We have identified 4 additional XLMR families with the ARX dup24 mutation from a panel of 11 XLMR families linked to Xp22.1. This finding makes the ARX dup24 mutation the most common mutation in nonsyndromic XLMR families linked to Xp22.1. As this mutation can be readily tested for using an automated sequencer, screening should be considered for any male with nonsyndromic MR of unknown etiology.

Chromosomes, Human, X↗
PubMed2005

A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor.

The renin-angiotensin system (RAS) is essential for blood pressure control and water-electrolyte balance. Until the discovery of the renin receptor, renin was believed to be mainly a circulating enzyme with a unique function, the cleavage of angiotensinogen. We report a unique mutation in the renin receptor gene (ATP6AP2) present in patients with X-linked mental retardation and epilepsy (OMIM no. 300423), but absent in 1200 control X-chromosomes. A silent mutation (c.321C>T, p.D107D) residing in a putative exonic splicing enhancer site resulted in inefficient inclusion of exon 4 in 50% of renin receptor mRNA, as demonstrated by quantitative RT-PCR. Analysis of membrane associated-receptor molecular forms showed the presence of full-length and truncated proteins in the patient. Functional analysis demonstrated that the mutated receptor could bind renin and increase renin catalytic activity, similar to the wild-type receptor, but resulted in a modest and reproducible impairment of ERK1/2 activation. Thus, our findings confirm the importance of the RAS in cognitive processes and indicate a novel specific role for the renin receptor in cognitive functions and brain development.

Alternative Splicing↗
PubMed2005

Mutation in the 5' alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome.

The Chudley-Lowry syndrome (ChLS, MIM 309490) is an X-linked recessive condition characterized by moderate to severe mental retardation, short stature, mild obesity, hypogonadism, and distinctive facial features characterized by depressed nasal bridge, anteverted nares, inverted-V-shaped upper lip, and macrostomia. The original Chudley-Lowry family consists of three affected males in two generations. Linkage analysis had localized the gene to a large interval, Xp21-Xq26 and an obligate carrier was demonstrated to have highly skewed X inactivation. The combination of the clinical phenotype, consistent with that of the patients with ATR-X syndrome, the skewed X-inactivation pattern in a carrier female, as well as the mapping interval including band Xq13.3, prompted us to consider the XNP/ATR-X gene being involved in this syndrome. Using RT-PCR analysis, we screened the entire XNP/ATR-X gene and found a mutation in exon 2 (c.109C > T) giving rise to a stop codon at position 37 (p.R37X). Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against XNP/ATR-X showed the protein to be present in lymphoblastoid cells from one affected male, despite the premature stop codon. To explain these discordant results, we further analyzed the 5' region of the XNP/ATR-X gene and found three alternative transcripts, which differ in the presence or absence of exon 2, and the length of exon 1. Our data suggest that ChLS is allelic to the ATR-X syndrome with its less severe phenotype being due to the presence of some XNP/ATR-X protein.

Alternative Splicing↗
PubMed2005

Advances in X-linked mental retardation.

PURPOSE OF REVIEW: Mutations in genes on the X chromosome rival chromosome aberrations as a cause of mental retardation. Progress in the clinical and molecular delineation of X-linked mental retardation has outpaced progress in understanding autosomal mental retardation. This is a result in large part of the identification of large families in which mental retardation has segregated in an X-linked pattern and the greater ease with which molecular technologies can be applied to hemizygosity in males. RECENT FINDINGS: About one-third of the estimated 165 genes associated with syndromal mutations of genes on the X chromosome and one-fourth of the estimated 100 genes associated with nonsyndromal mutations of genes on the X chromosome have been identified. In a number of instances, the same gene is responsible for syndromal and nonsyndromal mutations of genes on the X chromosome. The molecular delineation of mutations of genes on the X chromosome has allowed certain conditions to be lumped together on the basis of allelism and has caused others that appear clinical similar to remain separate. SUMMARY: The clinical and molecular advances have allowed X-linked mental retardation to be more clearly delineated, have provided the means of confirmatory laboratory testing, and have ushered in an era of carrier testing, prenatal diagnosis, and prevention strategies.

Carrier Proteins↗
PubMed2004

A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A.

The genetic contribution to autism is often attributed to the combined effects of many loci (ten or more). This conclusion is based in part on the much lower concordance for dizygotic (DZ) than for monozygotic (MZ) twins, and is consistent with the failure to find strong evidence for linkage in genome-wide studies. We propose that the twin data are compatible with oligogenic inheritance combined with a major, genetic or epigenetic, de novo component to the etiology. Based on evidence that maternal but not paternal duplications of chromosome 15q cause autism, we attempted to test the hypothesis that autism involves oligogenic inheritance (two or more loci) and that the Angelman gene (UBE3A), which encodes the E6-AP ubiquitin ligase, is one of the contributing genes. A search for epigenetic abnormalities led to the discovery of a tissue-specific differentially methylated region (DMR) downstream of the UBE3A coding exons, but the region was not abnormal in autism lymphoblasts or brain samples. Based on evidence for allele sharing in 15q among sib-pairs, abnormal DNA methylation at the 5'-CpG island of UBE3A in one of 17 autism brains, and decreased E6-AP protein in some autism brains, we propose a mixed epigenetic and genetic model for autism with both de novo and inherited contributions. The role of UBE3A may be quantitatively modest, but interacting proteins such as those ubiquitinated by UBE3A may be candidates for a larger role in an oligogenic model. A mixed epigenetic and genetic and mixed de novo and inherited (MEGDI) model could be relevant to other "complex disease traits".

Alleles↗
PubMed2004

Neural tube defects and associated anomalies in South Carolina.

BACKGROUND: Neural tube defects (NTDs) occur as isolated malformations and in the company of other birth defects. This study was conducted to determine the frequency of coexisting anomalies and the relationship between them. METHODS: Since 1992, NTDs have been identified through prenatal and postnatal surveillance activities in South Carolina. The type of NTD and presence of associated anomalies were determined by prenatal ultrasound, postnatal and/or postmortem examination. RESULTS: During the ten-year period from 1992 to 2002, 564 NTDs were identified by the surveillance system. Seventeen percent of NTDs (98/564) had associated malformations. In approximately half (n = 51) of these cases, the NTDs and associated anomalies were components of a recognizable syndrome. In the remaining cases (n = 47), no syndrome was identified or suspected, but the associated anomalies were believed in most instances to be secondary to space limitation or neural crest abnormalities imposed by the NTD. CONCLUSION: Seventeen percent of NTDs in South Carolina have associated malformations. In most cases, the associated anomalies are considered either components of a multiple malformation syndrome or secondary to the NTD.

Adult↗
PubMed2003

Genetic syndromes among individuals with mental retardation.

Individuals with mental retardation more commonly have malformations and other structural anomalies than individuals without mental retardation. In many cases, the associated anomalies comprise recognizable syndromes caused by genetic or environmental insults. To co-occurrence of structural anomalies with mental retardation thus assists in the diagnostic evaluation, particularly in infants and young children. The coexistence of structural and mental abnormalities also suggests that both originated in the embryonic period of development.

Adolescent↗
PubMed2003

A genomic rearrangement resulting in a tandem duplication is associated with split hand-split foot malformation 3 (SHFM3) at 10q24.

Split hand-split foot malformation (SHFM) is characterized by hypoplasia/aplasia of the central digits with fusion of the remaining digits. SHFM is usually an autosomal dominant condition and at least five loci have been identified in humans. Mutation analysis of the DACTYLIN gene, suspected to be responsible for SHFM3 in chromosome 10q24, was conducted in seven SHFM patients. We screened the coding region of DACTYLIN by single-strand conformation polymorphism and sequencing, and found no point mutations. However, Southern, pulsed field gel electrophoresis and dosage analyses demonstrated a complex rearrangement associated with a approximately 0.5 Mb tandem duplication in all the patients. The distal and proximal breakpoints were within an 80 and 130 kb region, respectively. This duplicated region contained a disrupted extra copy of the DACTYLIN gene and the entire LBX1 and beta-TRCP genes, known to be involved in limb development. The possible role of these genes in the SHFM3 phenotype is discussed.

Abnormalities, Multiple↗