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1.
Eur J Med Genet ; 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31048079

RESUMO

Achondroplasia (ACH) and hypochondroplasia (HCH) are genetic bone disorders known to be caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Both conditions share radiographic and phenotypical features. HCH is a milder form of ACH. Most individuals with ACH have the recurrent mutation (p.Gly380Arg) in the transmembrane (TM) domain of the receptor and individuals with HCH show the common mutation (p.Asn540Lys) in the tyrosine kinase 1 (TK1) region. Other rare mutations have been reported, however no additional hot-spot has been identified. We report an 8-month-old infant, with the heterozygous mutation, c.1043C > G, leading to an amino acid change from serine at 348 to cysteine (p.Ser348Cys). Clinical diagnosis of the patient is intertwined with "mild ACH" or "severe HCH". He did not demonstrate acanthosis nigricans (AN). This mutation has been reported in two different patients and it is located in the Ig-III domain of the FGFR3 region near other mutations associated with ACH. Among the two the 8-year old one also demonstrated AN without evindece of hyperinsulinem. This report emphasizes the benefit of whole gene sequencing for FGFR3 in individuals with suspected "mild ACH/severe HCH". This child will be monitored for future occurrence of AN.

2.
Am J Med Genet A ; 179(7): 1157-1172, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30980518

RESUMO

3M syndrome is characterized by severe pre- and postnatal growth retardation, typical facial features, and normal intelligence. Homozygous or compound heterozygous mutations in either CUL7, OBSL1, or CCDC8 have been identified in the etiology so far. Clinical and molecular features of 24 patients (23 patients and a fetus) from 19 unrelated families with a clinical diagnosis of 3M syndrome were evaluated and genotype-phenotype correlations were investigated with the use of DNA sequencing, chromosomal microarray, and whole exome sequencing accordingly. A genetic etiology could be established in 20 patients (n = 20/24, 83%). Eleven distinct CUL7 or OBSL1 mutations, among which eight was novel, were identified in 18 patients (n = 18/24, 75%). Ten patients had CUL7 (n = 10/18, 56%) while eight had OBSL1 (n = 8/18, 44%) mutations. Birth weight and height standard deviation scores at admission were significantly (p < 0.05) lower in patients with CUL7 mutation compared to that of patients with OBSL1 mutation. Two patients with a similar phenotype had a de novo 20p13p deletion involving BMP2. No genetic etiology could be established in four patients (n = 4/28, 17%). This study yet represents the largest cohort of 3M syndrome patients from a single center in Turkey. Microdeletions involving BMP2 may cause a phenotype similar to 3M syndrome with some distinctive features. Larger cohort of patients are required to establish genotype-phenotype correlations in 3M syndrome.

3.
BMC Med Genet ; 20(1): 15, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642273

RESUMO

BACKGROUND: Autosomal recessive nail dysplasia is characterized by thick and hard nails with a very slow growth on the hands and feet. Mutations in FZD6 gene were found to be associated with autosomal recessive nail dysplasia in 2011. Presently, only seven mutations have been reported in FZD6 gene; five mutations are clustered in the C-terminus, one is at the seventh transmembrane domain, and another is at the very beginning of third extracellular loop. METHODS: Whole exome sequencing (WES) was applied to the index case, her one affected sister and her healthy consanguineous parents. The mutation was verified via Sanger sequencing. Molecular dynamics simulations of the predicted structures of native and mutant proteins were compared to gain insight into the pathogenicity mechanism of the mutation. RESULTS: Here, we report a homozygous 8 bp deletion mutation, p.Gly559Aspfs*16; c.1676_1683delGAACCAGC, in FZD6 gene which causes a frameshift and creates a premature stop codon at position 16 of the new reading frame. Our molecular dynamics calculations predict that the pathogenicity of this frameshift mutation may be caused by the change in entropy of the protein with negative manner, disturbing the C-terminal domain structure, and hence interaction partners of FZD6. CONCLUSION: We identified a homozygous deletion mutation in FZD6 in a consanguineous Turkish family with nail dysplasia. We also provide a molecular mechanism about the effects of the deletion on the protein structure and its possible motions. This study provides a pathogenicity mechanism for this mutation in nail dysplasia for the first time.


Assuntos
Receptores Frizzled/genética , Predisposição Genética para Doença , Mutação , Unhas Malformadas/genética , Adulto , Sequência de Aminoácidos , Códon sem Sentido , Consanguinidade , Feminino , Mutação da Fase de Leitura , Receptores Frizzled/química , Estudos de Associação Genética , Homozigoto , Humanos , Modelos Moleculares , Linhagem , Conformação Proteica , Análise de Sequência , Deleção de Sequência , Turquia
5.
Genet Med ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30349098

RESUMO

PURPOSE: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. METHODS: Clinicians entered clinical data in an extensive web-based survey. RESULTS: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. CONCLUSION: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

6.
Nat Genet ; 50(8): 1093-1101, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30013181

RESUMO

Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The αN-catenin paralog, αE-catenin, acts as a switch regulating the balance between ß-catenin and Arp2/3 actin filament activities1. Loss of αN-catenin did not affect ß-catenin signaling, but recombinant αN-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of αN-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons.

7.
Eur J Obstet Gynecol Reprod Biol ; 221: 76-80, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29275276

RESUMO

OBJECTIVE: To determine frequency of fragile X associated premature ovarian insufficiency (FXPOI) among Turkish premutation carriers. STUDY DESIGN: FMR1 premutation is the single most common genetic cause of POI (FXPOI). Fragile X Registry at Hacettepe University has been reviewed for the frequency of FXPOI among female premutation carriers. Since 1991 when FMR1 testing was available, 760 individuals from 243 families have been registered. Actual data on menstrual status of female premutation carriers were gathered and analysed. RESULTS: Among 314 premutation-bearing females in the cohort, 268 could be reached for an update of their menstrual history; 107 adults were 40 or younger and 156 were older than 40 years of age, whereas the remaining 5 patients were prepubertal. Among 263 postpubertal females with premutations, 90 women stopped menstruating before or at 40 years of age (premature ovarian failure - POF), constituting 34.2% of our cohort. Additionally, one carrier of a gray zone allele experienced FXPOI. History of twinning was present once in 18 women (5.7%) and twice in two women (0.6%), one of the latter interestingly bearing a full-mutation. CONCLUSIONS: FXPOI rates in the present cohort are higher than those reported in other populations. Higher FXPOI rates in Turkish premutation carriers might be a reflection of younger mean menopause age and higher POI rates in otherwise healthy Turkish women. Since POI is much more frequent among premutation carriers than in general population, testing for CGG repeat expansions in FMR1 should be included in the work-up.


Assuntos
Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Mutação , Insuficiência Ovariana Primária/genética , Adulto , Alelos , Estudos de Coortes , Feminino , Frequência do Gene , Humanos , Pessoa de Meia-Idade , Fenótipo , Sistema de Registros , Turquia
10.
Turk J Pediatr ; 60(5): 506-513, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30968633

RESUMO

Bilgin B, Kabaçam S, Taskiran E, Simsek-Kiper PÖ, Alanay Y, Boduroglu K, Utine GE. Epigenotype and phenotype correlations in patients with Beckwith-Wiedemann syndrome. Turk J Pediatr 2018; 60: 506-513. Beckwith-Wiedemann Syndrome (BWS) is one of the most common overgrowth syndromes. Cancer predisposition is an important feature of this clinically heterogeneous syndrome. Patients may have fetal and early childhood overgrowth, hemihyperplasia, macroglossia, facial dysmorphic features, abdominal wall defects, visceromegaly, and anomalies of the heart and the kidneys. Various previous investigations showed that heterogeneous molecular etiology may contribute to clinical variability and that epigenotype-phenotype correlations exist in BWS. This study was performed to detect the molecular etiology in 28 patients with BWS, to search for epigenotype-phenotype correlations and to provide appropriate individualized multidisciplinary approach. Four different molecular etiology groups were determined based on testing for copy number analysis and methylation status at 11p15. Sequencing for CDKN1C mutations were also performed. Groups were compared for various clinical findings. Differences between groups were not statistically significant owing to the small number of patients in individual groups. Statistical studies for epigenotype-phenotype correlations showed significance for only anterior ear lobe creases, visceromegaly and embryonal tumors. Additionally, one interesting patient had a mesenchymal tumor. Anticipating follow-up is clinically important in BWS.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Síndrome de Beckwith-Wiedemann/diagnóstico , Criança , Pré-Escolar , Metilação de DNA , Feminino , Impressão Genômica , Genótipo , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase Multiplex/métodos , Mutação , Fenótipo , Análise de Sequência de DNA/métodos
11.
J Bone Miner Res ; 32(6): 1309-1319, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28177155

RESUMO

Lysine hydroxylation of type I collagen telopeptides varies from tissue to tissue, and these distinct hydroxylation patterns modulate collagen cross-linking to generate a unique extracellular matrix. Abnormalities in these patterns contribute to pathologies that include osteogenesis imperfecta (OI), fibrosis, and cancer. Telopeptide procollagen modifications are carried out by lysyl hydroxylase 2 (LH2); however, little is known regarding how this enzyme regulates hydroxylation patterns. We identified an ER complex of resident chaperones that includes HSP47, FKBP65, and BiP regulating the activity of LH2. Our findings show that FKBP65 and HSP47 modulate the activity of LH2 to either favor or repress its activity. BiP was also identified as a member of the complex, playing a role in enhancing the formation of the complex. This newly identified ER chaperone complex contributes to our understanding of how LH2 regulates lysyl hydroxylation of type I collagen C-telopeptides to affect the quality of connective tissues. © 2017 American Society for Bone and Mineral Research.


Assuntos
Colágeno Tipo I/metabolismo , Proteínas de Choque Térmico HSP47/metabolismo , Proteínas de Choque Térmico/metabolismo , Lisina/metabolismo , Complexos Multiproteicos/metabolismo , Peptídeos/metabolismo , Pró-Colágeno/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Linhagem Celular , Estabilidade Enzimática , Humanos , Hidroxilação , Espectrometria de Massas , Camundongos , Modelos Biológicos , Mutação/genética , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismo , Ressonância de Plasmônio de Superfície
12.
Am J Hum Genet ; 100(2): 216-227, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28065471

RESUMO

Defects of the V-type proton (H+) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of cutis laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic cutis laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.


Assuntos
Cútis Laxa/genética , Mutação de Sentido Incorreto , ATPases Vacuolares Próton-Translocadoras/genética , Adolescente , Alelos , Sequência de Aminoácidos , Estudos de Casos e Controles , Criança , Feminino , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Glicosilação , Complexo de Golgi/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Conformação Proteica , Transporte Proteico , Espectrometria de Massas em Tandem
13.
Am J Med Genet A ; 170(12): 3231-3236, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27531620

RESUMO

Here we summarize the clinical and molecular findings in a 68-year-old female with dysmorphic features, mild-to-moderate intellectual disability, and behavioral findings suggesting autism spectrum disorder. SNP array analysis demonstrated a 257 kb deletion comprising exon 6 of AUTS2. This clinical report provides the natural history in the eldest patient yet to be reported, and complements the existing evidence suggesting that disruption of the AUTS2 leads to a recently delineated neurodevelopmental phenotype with a wide spectrum, namely "AUTS2 Syndrome." © 2016 Wiley Periodicals, Inc.


Assuntos
Estudos de Associação Genética , Mutação , Fenótipo , Proteínas/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Idoso , Facies , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Radiografia , Síndrome
14.
Am J Med Genet A ; 170(7): 1889-94, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27144803

RESUMO

Epispadias and exstrophy of the cloaca, also known as OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects), respectively constitute the most benign and severe ends of the bladder exstrophy-epispadias complex (BEEC) spectrum. In 2009, El-Hattab et al. reported the first patient with OEIS complex associated with a chromosome 1p36 deletion. Here we report a second patient with 1p36 deletion who also has classic bladder exstrophy, supporting the possible role of genes in this region in the development of BEEC. The absence of omphalocele and imperforate anus in our patient places him toward classic bladder exstrophy while presence of spina bifida and the absence of coccyx suggest an overlap with OEIS complex. An additional differential diagnosis is the pentalogy of Cantrell in our patient as he also has a diaphragmatic hernia and an incomplete sternum. This is the second observation of a ventral midline birth defect in association with 1p36 deletion syndrome, following El-Hattab et al.'s report [2009]. The three genes (NOCL2, DVL1, and MMP23B) discussed as possible candidates are also among the deleted ones in our patient, supporting the possible role of these genes in BEEC spectrum. © 2016 Wiley Periodicals, Inc.


Assuntos
Anormalidades Múltiplas/genética , Anus Imperfurado/genética , Transtornos Cromossômicos/genética , Epispadia/genética , Hérnia Umbilical/genética , Escoliose/genética , Anormalidades Urogenitais/genética , Anormalidades Múltiplas/fisiopatologia , Anus Imperfurado/fisiopatologia , Extrofia Vesical/fisiopatologia , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/fisiopatologia , Cromossomos Humanos Par 1/genética , Epispadia/fisiopatologia , Feminino , Estudos de Associação Genética , Hérnia Umbilical/fisiopatologia , Humanos , Masculino , Gravidez , Diagnóstico Pré-Natal , Escoliose/fisiopatologia , Anormalidades Urogenitais/fisiopatologia
16.
Genet Med ; 18(9): 882-91, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26765342

RESUMO

PURPOSE: The Ehlers-Danlos syndrome (EDS), dermatosparaxis type, is a recessively inherited connective tissue disorder caused by deficient activity of ADAMTS-2, an enzyme that cleaves the aminoterminal propeptide domain of types I, II, and III procollagen. Only 10 EDS dermatosparaxis patients have been reported, all presenting a recognizable phenotype with characteristic facial gestalt, extreme skin fragility and laxity, excessive bruising, and sometimes major complications due to visceral and vascular fragility. METHODS: We report on five new EDS dermatosparaxis patients and provide a comprehensive overview of the current knowledge of the natural history of this condition. RESULTS: We identified three novel homozygous loss-of-function mutations (c.2927_2928delCT, p.(Pro976Argfs*42); c.669_670dupG, p.(Pro224Argfs*24); and c.2751-2A>T) and one compound heterozygous mutation (c.2T>C, p.? and c.884_887delTGAA, p.(Met295Thrfs26*)) in ADAMTS2 in five patients from four unrelated families. Three of these displayed a phenotype that was strikingly milder than that of previously reported patients. CONCLUSION: This study expands the clinical and molecular spectrum of the dermatosparaxis type of EDS to include a milder phenotypic variant and stresses the importance of good clinical criteria. To address this, we propose an updated set of criteria that accurately captures the multisystemic nature of the dermatosparaxis type of EDS.Genet Med 18 9, 882-891.


Assuntos
Proteínas ADAMTS/genética , Síndrome de Ehlers-Danlos/genética , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/patologia , Feminino , Humanos , Masculino , Mutação , Fenótipo
17.
Turk J Pediatr ; 58(5): 541-544, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28621098

RESUMO

Hyperinsulinism/hyperammonemia (HI/HA) syndrome is a rare disorder presented with recurrent hypoglycemia and elevated serum ammonia, which may lead to development delays, permanent neurologic damages, if it remains underdiagnosed. It is caused by activating mutations in the GLUD1 gene which encodes the intra-mitochondrial enzyme glutamate dehydrogenase (GDH). HI/HA syndrome is considered the second most common form of hyperinsulinism (HI), and usually associated with epileptic seizures, mental retardation and generalized dystonia. We reported a patient who was diagnosed as HI/HA with multiple episodes of seizures; and previously had been diagnosed and treated for epilepsy. She has heterozygous mutation in GLUD1 gene. Treatment with diazoxide enabled complete resolution of the seizures. One year later, when her brother was six months old, he was also diagnosed with HI/HA. Later, the same mutation of GLUD1 was detected in both her father and brother too.


Assuntos
Glutamato Desidrogenase/genética , Hiperinsulinismo/diagnóstico , Hipoglicemia/diagnóstico , Convulsões/etiologia , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Feminino , Heterozigoto , Humanos , Masculino , Mutação
18.
Eur J Hum Genet ; 24(1): 51-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25944382

RESUMO

We report on seven novel patients with a submicroscopic 22q12 deletion. The common phenotype constitutes a contiguous gene deletion syndrome on chromosome 22q12.1q12.2, featuring NF2-related schwannoma of the vestibular nerve, corpus callosum agenesis and palatal defects. Combining our results with the literature, eight patients are recorded with palatal defects in association with haploinsufficiency of 22q12.1, including the MN1 gene. These observations, together with the mouse expression data and the finding of craniofacial malformations including cleft palate in a Mn1-knockout mouse model, suggest that this gene is a candidate gene for cleft palate in humans.


Assuntos
Agenesia do Corpo Caloso/genética , Deleção Cromossômica , Cromossomos Humanos Par 22 , Fissura Palatina/genética , Neuroma Acústico/genética , Proteínas Supressoras de Tumor/deficiência , Adolescente , Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/metabolismo , Animais , Criança , Pré-Escolar , Mapeamento Cromossômico , Fissura Palatina/diagnóstico , Fissura Palatina/metabolismo , Feminino , Expressão Gênica , Haploinsuficiência , Humanos , Masculino , Camundongos , Camundongos Knockout , Neuroma Acústico/diagnóstico , Neuroma Acústico/metabolismo , Análise de Sequência de DNA , Proteínas Supressoras de Tumor/genética
19.
Pediatr Dermatol ; 32(6): e263-6, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26446280

RESUMO

Hoyeraal-Hreidarsson syndrome is a rare telomere biology disorder that is recognized as a severe variant of dyskeratosis congenita. We present a Libyan boy with hematologic and neurologic abnormalities with typical dermatologic manifestations of dyskeratosis congenita. Death usually occurs before the age of 4 years as a result of pancytopenia or malignant transformation of mucocutaneous lesions. The boy presented survived longer than 5 years. Early recognition and appropriate genetic counseling are crucial because of the high mortality of this genetic disorder.


Assuntos
Disceratose Congênita/diagnóstico , Retardo do Crescimento Fetal/diagnóstico , Deficiência Intelectual/diagnóstico , Microcefalia/diagnóstico , Pré-Escolar , Diagnóstico Diferencial , Disceratose Congênita/genética , Retardo do Crescimento Fetal/genética , Humanos , Deficiência Intelectual/genética , Imagem por Ressonância Magnética , Masculino , Microcefalia/genética , Fenótipo , Telômero/genética
20.
Orphanet J Rare Dis ; 10: 128, 2015 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-26419238

RESUMO

BACKGROUND: 3MC1 syndrome is a rare autosomal recessive disorder characterized by intellectual disability, short stature and distinct craniofacial, umbilical, and sacral anomalies. Five mutations in MASP1, encoding lectin complement pathway enzymes MASP-1 and MASP-3, have thus far been reported to cause 3MC1 syndrome. Only one previously reported mutation affects both MASP-1 and MASP-3, while the other mutations affect only MASP-3. METHODS: We evaluated six unrelated individuals with 3MC1 syndrome and performed Sanger sequencing for all coding exons of MASP1. We also measured complement lectin and alternative pathway activities in an affected individual's serum. RESULTS: We found two novel splice site mutations, c.1012-2A > G in one and c.891 + 1G > T in two probands, and three novel missense mutations, c.1451G > A (p.G484E), c.1657G > A (p.D553N), and c.1987G > T (p.D663Y). Missense mutations affect only MASP-3, while splice site mutations affect both MASP-1 and MASP-3. In a proband who is homozygous for c.891 + 1G > T, we detected a total lack of lectin complement pathway activity and a 2.5-fold lower alternative pathway activity. The phenotype observed in patients whose both MASP-1 and MASP-3 are affected and in those whose only MASP-3 is affected does not appear to be different. We observed structural brain abnormalities, neonatal tooth, a vascular anomaly and a solid lesion in liver as novel phenotypic features of 3MC1 syndrome. CONCLUSION: Novel mutations and additional phenotypic features expand the genotypic and phenotypic spectrum of 3MC1 syndrome. Although patients with MASP-1 dysfunction in addition to disrupted MASP-3 have an altered complement system, their disease phenotype is not different from those having only MASP-3 dysfunction.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Mutação/genética , Fenótipo , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Síndrome , Adulto Jovem
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