Smith-Magenis Syndrome Region Research Articles

The clinical spectrum associated with a chromosome 17 short arm proximal duplication (dup 17p11.2) in three patients

The p11.2-p12 region of human chromosome 17 is gene rich and composed of at least two genomically unstable domains: the Smith-Magenis syndrome region (17p11.2) and the Charcot-Marie-Tooth region (17p12), both of which are flanked by several low-copy repeat sequences. Homologous recombination between these flanking repeats results in either deletion- or duplication-associated phenotypes caused by a gene dosage effect. We report on the clinical phenotype of three patients presenting with either a 17p11.2 or 17p11.2p12 duplication, revealed by chromosome analysis and confirmed by fluorescent in situ hybridization analysis, high resolution genomic analysis of the 17p region using oligonucleotide array comparative genomic hybridization, and molecular studies with microsatellite markers. Two patients carry the 17p11.2 duplication, while the third one shows a larger duplication including the 17p12 region. The facial features observed in our patients include triangular face, full cheeks, smooth philtrum, thin upper lip, dental malocclusion, irregular eyebrows, and sparse hair, all of which are consistent with the pure proximal dup 17p phenotype. The patients' other clinical features are compared with previously published cases.

Detection and delineation of an unusual 17p11.2 deletion by array-CGH and refinement of the Smith–Magenis syndrome minimum deletion to ~650 kb

Smith–Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome and it is characterized by an interstitial deletion of chromosome 17p11.2. SMS patients have a distinct phenotype which is believed to be caused by haploinsufficiency of one or more genes in the associated deleted region. Five non-deletion patients with classical phenotypic features of SMS have been reported with mutations in the retinoic acid induced 1 ( RAI1) gene, located within the SMS critical interval. Happloinsufficiency of the RAI1 gene is likely to be the responsible gene for the majority of the SMS features, but other deleted genes in the SMS region may modify the overall phenotype in the patients with 17p11.2 deletions. SMS is usually diagnosed in the clinical genetic setting by FISH analysis using commercially available probes. We detected a submicroscopic deletion in 17p11.2 using array-CGH with a resolution of approximately 1 Mb in a patient with the SMS phenotype, who was not deleted for the commercially available SMS microdeletion FISH probe. Delineation of the deletion was performed using a 32K tiling BAC-array, containing 32,500 BAC clones. The deletion in this patient was size mapped to 2.7 Mb and covered the RAI1 gene. This case enabled the refinement of the SMS minimum deletion to ~650 kb containing eight putative genes and one predicted gene. In addition, it demonstrates the importance to investigate deletion of RAI1 in SMS patients.

Uncommon Deletions of the Smith-Magenis Syndrome Region Can Be Recurrent When Alternate Low-Copy Repeats Act as Homologous Recombination Substrates

Several homologous recombination "hotspots," or sites of positional preference for strand exchanges, associated with recurrent deletions and duplications have been reported within large low-copy repeats (LCRs). Recently, such a hotspot was identified in patients with the Smith-Magenis syndrome (SMS) common deletion of approximately 4 Mb or a reciprocal duplication within the KER gene cluster of the SMS-REP LCRs, in which 50% of analyzed strand exchanges resulting in deletion and 23% of those resulting in duplication occurred. Here, we report an additional recombination hotspot within LCR17pA and LCR17pD, which serve as alternative substrates for nonallelic homologous recombination that results in large (approximately 5 Mb) deletions of 17p11.2, which include the SMS region. Using polymerase-chain-reaction mapping of somatic cell hybrid lines, we refined the breakpoints of six deletions within these LCRs. Sequence analysis of the recombinant junctions revealed that all six strand exchanges occurred within a 524-bp interval, and four of them occurred within an AluSq/x element. This interval represents only 0.5% of the 124-kb stretch of 98.6% sequence identity between LCR17pA and LCR17pD. A search for potentially stimulating sequence motifs revealed short AT-rich segments flanking the recombination hotspot. Our findings indicate that alternative LCRs can mediate rearrangements, resulting in haploinsufficiency of the SMS critical region, and reimplicate homologous recombination as a major mechanism for genomic disorders.

Mouse cytosolic and mitochondrial deoxyribonucleotidases: cDNA cloning of the mitochondrial enzyme, gene structures, chromosomal mapping and comparison with the human orthologs

Two of the five known mammalian 5′-nucleotidases show a preference for the dephosphorylation of deoxynucleoside-5′-phosphates. One is a cytoplasmic enzyme (dNT-1), the other occurs in mitochondria (dNT-2). The human mitochondrial enzyme, recently discovered and cloned by us, is encoded by a nuclear gene located on chromosome 17 p11.2 in the critical region deleted in the Smith–Magenis syndrome (SMS), a genetic disease of unknown etiology. Looking for a model system to study the possible involvement of dNT-2 in the disease, we have cloned the cDNA of the mouse ortholog. The deduced protein sequence is 84% identical to the human ortholog, has a very basic NH2-terminus, a very high calculated probability of being imported into mitochondria and contains the DXDXT/V motif conserved among nucleotidases. Expression in Escherichiacoli of the predicted processed form of the protein produced an active deoxyribonucleotidase. We also identified in genomic sequences present in the data base the structures of the murine genes for the cytosolic and mitochondrial deoxyribonucleotidases (Nt5c and Nt5m). PAC clones for the two loci were isolated from a library and used for chromosomal localization by fluorescent in situ hybridization. Both genes map on chromosome 11: Nt5c at 11E and Nt5m at 11B, demonstrating the presence of the dNT-2 locus in the mouse shaker-2 critical region, the murine counterpart of the human SMS region. We performed pair-wise dot-plot and PIP (percent identity plot) analyses of mouse and human deoxyribonucleotidase genes, and found a strong conservation that extends also to some intronic sequences of possible regulatory significance.

Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs.

An approximately 4-Mb genomic segment on chromosome 17p11.2, commonly deleted in patients with the Smith-Magenis syndrome (SMS) and duplicated in patients with dup(17)(p11.2p11.2) syndrome, is flanked by large, complex low-copy repeats (LCRs), termed proximal and distal SMS-REP. A third copy, the middle SMS-REP, is located between them. SMS-REPs are believed to mediate nonallelic homologous recombination, resulting in both SMS deletions and reciprocal duplications. To delineate the genomic structure and evolutionary origin of SMS-REPs, we constructed a bacterial artificial chromosome/P1 artificial chromosome contig spanning the entire SMS region, including the SMS-REPs, determined its genomic sequence, and used fluorescence in situ hybridization to study the evolution of SMS-REP in several primate species. Our analysis shows that both the proximal SMS-REP (approximately 256 kb) and the distal copy (approximately 176 kb) are located in the same orientation and derived from a progenitor copy, whereas the middle SMS-REP (approximately 241 kb) is inverted and appears to have been derived from the proximal copy. The SMS-REP LCRs are highly homologous (>98%) and contain at least 14 genes/pseudogenes each. SMS-REPs are not present in mice and were duplicated after the divergence of New World monkeys from pre-monkeys approximately 40-65 million years ago. Our findings potentially explain why the vast majority of SMS deletions and dup(17)(p11.2p11.2) occur at proximal and distal SMS-REPs and further support previous observations that higher-order genomic architecture involving LCRs arose recently during primate speciation and may predispose the human genome to both meiotic and mitotic rearrangements.

DNA Rearrangements on Both Homologues of Chromosome 17 in a Mildly Delayed Individual with a Family History of Autosomal Dominant Carpal Tunnel Syndrome

Disorders known to be caused by molecular and cytogenetic abnormalities of the proximal short arm of chromosome 17 include Charcot-Marie-Tooth disease type 1A (CMT1A), hereditary neuropathy with liability to pressure palsies (HNPP), Smith-Magenis syndrome (SMS), and mental retardation and congenital anomalies associated with partial duplication of 17p. We identified a patient with multifocal mononeuropathies and mild distal neuropathy, growth hormone deficiency, and mild mental retardation who was found to have a duplication of the SMS region of 17p11.2 and a deletion of the peripheral myelin protein 22 (PMP22) gene within 17p12 on the homologous chromosome. Further molecular analyses reveal that the dup(17)(p11.2p11.2) is a de novo event but that the PMP22 deletion is familial. The family members with deletions of PMP22 have abnormalities indicative of carpal tunnel syndrome, documented by electrophysiological studies prior to molecular analysis. The chromosomal duplication was shown by interphase FISH analysis to be a tandem duplication. These data indicate that familial entrapment neuropathies, such as carpal tunnel syndrome and focal ulnar neuropathy syndrome, can occur because of deletions of the PMP22 gene. The co-occurrence of the 17p11.2 duplication and the PMP22 deletion in this patient likely reflects the relatively high frequency at which these abnormalities arise and the underlying molecular characteristics of the genome in this region.

Duplication 17p11.2 in two patients: clinical features and molecular cytogenetic findings

Since patients with duplications or deletions involving the Smith-Magenis syndrome (SMS) region at 17p11.2 are thought to arise by the same mechanism of unequal recombination between a repeat sequence that flanks the SMS region (Chen et al., 1997), it is surprising that the duplication patients have been so rarely reported (Magenis et al., 1986; Kozma et al., 1991, Brown et al., 1996; Chen et al., 1997 and 1998; Summers et al., 1998). These patients are most likely underdiagnosed because of lack of defined clinical features and subtlety of the duplication with routine cytogenetic studies. We report two additional patients and review the common physical features in this duplication syndrome.Patient 1 is an 11 month old male with postnatal growth retardation, length at mean for 5 months, and head circumference average for 6 months. He has ptosis of the left eyelid, narrow nose and palate, small mandible, sacral dimple, overlapping toes, decreased tone, and global developmental delay. Patient 2 is a 6 year old female with a history of failure to thrive in early childhood and developmental delay. Height, weight, and head circumference are at the 50th percentile; she has upslanting, narrow palpebral fissures, broad eyebrows, distal joint laxity, and normal neurologic exam. Developmental testing at age 6 showed a full scale IQ of 65, with performance IQ 60 and verbal IQ 78 and behavior consistent with attention deficit hyperactivity disorder.Cytogenetic analyses with G-banding showed duplication of 17p11.2 with a narrow extra gray band in the middle of the G-negative area in the p11.2 region. The duplication was confirmed with a FISH assay using the D17S258 probe (Oncor) for the SMS region. The D17S122 cosmid probe (Oncor), which hybridizes within the region that is duplicated in Charcot-Marie-Tooth type 1A patients, showed a single signal on each chromosome 17 indicating that this region is not duplicated.Comparison of facial features reveals striking similarities between patient 2 and the patient reported by Magenis. It also appears that despite significant early problems with weight gain and development, these patients have fewer problems as they get older and may function in the low normal to borderline range. Detailed clinical descriptions of patients with duplications of 17p11.2 will be helpful in further delineation and recognition of this duplication syndrome.

The brain finger protein gene (ZNF179), a member of the RING finger family, maps within the Smith-Magenis syndrome region at 17p11.2

Smith-Magenis syndrome (SMS) is caused by a microdeletion of 17p11.2 and comprises developmental and growth delay, facial abnormalities, unusual behavior and sleep problems. This phenotype may be due to haploinsufficiency of several contiguous genes. The human brain finger protein gene (ZNF179), a member of the RING finger protein family, has been isolated and mapped to 17p11.2. FISH analyses of metaphase or interphase chromosomes of 6 patients with SMS show that ZNF179 was deleted in one of the 2 homologs (17p11.2), indicating a possible association of the defect of this gene with the pathogenesis of SMS. Furthermore, using a prophase FISH ordering system, we sublocalized ZNF179 proximally to LLGL which lies on the critical region for SMS.

The Smith-Magenis syndrome [del(17)p11.2]: Clinical review and molecular advances

The Smith-Magenis syndrome (SMS) is a multiple congenital anomaly, mental retardation syndrome associated with a deletion of chromosome 17p11.2. Since the recognition of this disorder as a clinical entity in 1982, the phenotypic features of SMS have been well described. Unfortunately, the often subtle physical and chromosomal findings of SMS may preclude the diagnosis in some affected individuals. This article offers a comprehensive review of more than 100 SMS patients whose cases have been reported, including details of the more recently studied clinical aspects of SMS. SMS has been postulated to be a contiguous gene deletion syndrome. Currently, only a few genes have been mapped to the SMS critical region. Further research (including genotype-phenotype correlation) is needed to identify the gene or genes that, when deleted, cause this disorder. Although the molecular etiology of SMS is unknown, recent investigations have identified multiple repetitive sequences within the SMS region. As described in other human disorders, repetitive sequences may be involved in homologous recombination and cause deletion. The advances in the molecular dissection of the SMS region are described, and hypotheses regarding the molecular mechanisms of SMS are offered. Parallels are made between the SMS region and other regions in the human genome where the molecular etiologies of diseases have been elucidated. © 1996 Wiley-Liss, Inc.

The gene for a human microfibril-associated glycoprotein is commonly deleted in Smith-Magenis syndrome patients.

Smith-Magenis syndrome (SMS) is a clinically recognizable multiple congenital anomaly/mental retardation syndrome associated with deletion of chromosome 17p11.2. Here we report the identification of a novel gene encoding a human microfibril-associated glycoprotein (MFAP4), which has been mapped to the SMS region. A full-length cDNA corresponding to this gene has been sequenced, and reveals a coding region of 255 amino acids. MFAP4 has a fibrinogen-like domain and shares a high level of sequence homology to a fragment of a bovine 36 kDa microfibril-associated glycoprotein. The N-terminus of the protein bears an Arg-Gly-Asp sequence that serves as the ligand motif for cell surface receptor integrin. These structural features of MFAP4 suggest that it is an extracellular matrix protein involved in cell adhesion or intercellular interactions. Deletion analysis has been conducted on 31 SMS patients by polymerase chain reaction and Southern analysis of somatic cell hybrids retaining the del(17)(p11.2) chromosome or by fluorescence in situ hybridization. The MFAP4 locus is deleted in 30 of 31 SMS patients. Thus, the function of this gene must be considered in the pathogenesis of SMS. Given our previous hypothesis that SMS is a contiguous gene syndrome, complete and exhaustive definition of the critical deletion interval and a thorough phenotype-genotype correlation is required to demonstrate the role and importance of the MFAP4 gene in SMS.