Sirpa Ala-Mello's research while affiliated with Helsinki University Central Hospital and other places
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Publications (33)
Analyses in our diagnostic DNA laboratory include genes involved in autosomal recessive (AR) lysosomal storage disorders such as glycogenosis type II (Pompe disease) and mucopolysaccharidosis type I (MPSI, Hurler disease). We encountered 4 cases with apparent homozygosity for a disease-causing sequence variant that could be traced to one parent onl...
Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high-impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We found that the enrichment of a rare chromosome 22q11.22 dele...
Background
Diagnostic analysis of patients with developmental disorders has improved over recent years largely due to the use of microarray technology. Array methods that facilitate copy number analysis have enabled the diagnosis of up to 20% more patients with previously normal karyotyping results. A substantial number of patients remain undiagnos...
Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been identified in female patients with early onset epileptic encephalopathy and severe mental retardation with a Rett-like phenotype. Subsequently CDKL5 mutations were shown to be associated with more diverse phenotypes including mild epilepsy and autism without epilepsy. Furthermor...
We report on the results of an array comparative genomic hybridization (array CGH) study of 150 karyotypically normal Finnish patients with idiopathic mental retardation and/or dysmorphic features and/or malformations. Using high-resolution microarray analysis, we sought to identify clinically relevant microdeletions and microduplications in these...
Many idiopathic epilepsy syndromes have a characteristic age dependence, the underlying molecular mechanisms of which are largely unknown. Here we propose a mechanism that can explain that epileptic spells in benign familial neonatal-infantile seizures occur almost exclusively during the first days to months of life. Benign familial neonatal-infant...
Objective:
The aim was to identify chromosomal regions possibly involved in the development of orofacial clefts and to compare syndromic cleft phenotypes with previous reports.
Design:
We have retrospectively gathered and analyzed chromosomal aberrations and phenotypes of Finnish cleft patients treated at the Cleft and Craniofacial Centre, Helsi...
Focal dermal hypoplasia (FDH), Goltz or Goltz-Gorlin syndrome, is an X-linked dominant multisystem disorder characterized primarily by involvement of the skin, skeletal system and eyes. We screened for mutations in the PORCN gene in eight patients of Belgian and Finnish origin with firm clinical suspicion of FDH. First, we performed quantitative PC...
Many idiopathic epilepsy syndromes have a characteristic age dependence, the underlying molecular mechanisms of which are largely unknown. Here we propose a mechanism which can explain that epileptic spells in benign familial neonatal-infantile seizures (BFNIS) occur almost exclusively during the first days to months of life. BFNIS is caused by mut...
Microtia can be defined as a malformation of the auricle with varying severity. In the majority of patients it is combined with atresia or stenosis of the external auditory canal. The prevalence of microtia in Finland is approx. 4 out of 10000. Associated anomalies should be actively seeked and excluded. Approximately 70% of the patients seem to be...
The oculoauriculovertebral anomaly (OAV) or Goldenhar syndrome is a malformation complex that has been described in several chromosomal rearrangements. Among them a deletion of the terminal 5p has recurred in seven previous patients. We wish to report on an additional such patient in order to reinforce the significance of this genomic region in the...
Autosomal dominant CHARGE syndrome (OMIM no. 214800) is characterized by choanal atresia or cleft lip or palate, ocular colobomas, cardiovascular malformations, retardation of growth, ear anomalies, and deafness, and is caused by mutations in the CHD7 gene. Here, we describe the outcome of a molecular genetic analysis in 18 Finnish and 56 German pa...
To study the inheritance of microtia in the Finnish population, identify families for genetic linkage analyses and compare the phenotype between sporadic and familial patients.
Retrospective case series and patient questionnaire of 109 microtia patients referred for reconstruction of the earlobe to the Helsinki University Central Hospital during th...
To compare the characteristics of microtia in Finland and in other populations.
Retrospective case series and patient questionnaire of 190 microtia patients referred for reconstruction of the earlobe to the Helsinki University Central Hospital during the years 1980-2005.
The prevalence in Finland is 4.34/10,000 and varied in other populations from...
We investigated the prevalence of mutations in the PHD finger protein 8 (PHF8) gene in X-linked mental retardation (XLMR) and facial cleft starting from the original cohort of 7712 patients operated on since 1 January 1950 for cleft lip/cleft palate in the Cleft Centre at the Helsinki University Hospital. From this nationwide material, 18 patients...
Mowat-Wilson Syndrome is a recently delineated mental retardation syndrome usually associated with multiple malformations and a recognizable facial phenotype caused by defects of the transcriptional repressor ZFHX1B. To address the question of clinical and mutational variability, we analysed a large number of patients with suspected Mowat-Wilson Sy...
We report the follow-up data on the first Finnish patient with the Floating-Harbor syndrome (FHS) reported by us in 1996 at the age of 6 years (Ala-Mello and Peippo. We also discuss the diagnostic criteria of FHS, with a critical review of the literature.
Severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) is a rare disorder occurring in young children often without a family history of a similar disorder. The earliest disease manifestations are usually fever-associated seizures. Later in life, patients display different types of afebrile seizures including myoclonic seizures. Arrest of ps...
For nephronophthisis (NPHP), the primary genetic cause of chronic renal failure in young adults, three loci have been mapped. To identify a new locus for NPHP, we here report on total-genome linkage analysis in seven families with NPHP, in whom we had excluded linkage to all three known NPHP loci. LOD scores >1 were obtained at nine loci, which wer...
Autosomal-dominant medullary cystic kidney disease (ADMCKD) is characterized by the development of cysts at the corticomedullary border of the kidneys. It resembles nephronophthisis (NPH) with an autosomal-recessive mode of inheritance. Genetic linkage has been shown either on chromosome 1q21 (ADMCKD1) or 16p12 (ADMCKD2), and families exist who are...
Nephronophthisis (NPH) is a chronic tubulointerstitial nephritis leading to terminal renal insufficiency. The disease is heterogeneous, but usually the inheritance pattern is autosomal recessive. In 80% of cases, the disease is caused by a homozygous deletion in NPHP1 gene in chromosome 2q13. Ulcerative colitis is an inflammatory bowel disease with...
A new type of nephronophthisis (NPH) has been recently identified in a large Venezuelan kindred: adolescent nephronophthisis (NPH3) causes end-stage renal disease (ESRD) at a median age of 19 years. The responsible gene (NPHP3) maps to 3q21-q22. NPH3 shares with juvenile nephronophthisis (NPH1) the same disease manifestations such as polyuria, poly...
Nephronophthisis--medullary cystic kidney disease is a progressive chronic tubulointerstitial nephritis leading to terminal renal failure. About two thirds of the patients with familial juvenile nephronophthisis, an autosomal recessive disease, have a homozygous deletion at the gene locus on 2q13. Through a nationwide search, 59 patients were ascer...
Nail-patella syndrome (NPS), a pleiotropic disorder exhibiting autosomal dominant inheritance, has been studied for >100 years. Recent evidence shows that NPS is the result of mutations in the LIM-homeodomain gene LMX1B. To determine whether specific LMX1B mutations are associated with different aspects of the NPS phenotype, we screened a cohort of...
Familial juvenile nephronophthisis (NPH) is an autosomal recessive tubulointerstitial kidney disease associated with formation of medullary and corticomedullary cysts. It progresses to end stage renal failure and its biochemical defect is unknown. An NPH locus has been assigned to a 2 cM interval on chromosome 2q13 by linkage studies. Homozygous de...
Hermansky-Pudlak syndrome (HPS) is a rare, autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles-melanosomes, platelet-dense granules, and lysosomes. As reported elsewhere, we mapped the human HPS gene to chromosome segment 10q23, positionally clo...
To evaluate progressive US changes in the kidneys of patients with familial juvenile nephronophthisis (NPH), an autosomal recessive progressive kidney disease with polyuria, polydipsia, anemia and growth retardation.
The data from 29 US investigations of 5 boys and 2 girls comprised findings relating to kidney size, echogenicity of the kidney paren...
Familial juvenile nephronophthisis (NPH) is a hereditary form of chronic tubulointerstitial nephritis with onset in childhood. About one-third of patients develop anaemia before renal insufficiency. We investigated the pathogenetic mechanisms leading to anaemia by comparing 6 patients with NPH and 12 reference patients with other renal diseases. We...
A 6-year-old boy with the Floating-Harbor syndrome (F-HS) is described. We propose that his exceptionally high-pitched voice and supernumerary upper incisor are additional diagnostic signs of F-HS. The elevated gliadin antibody levels suggest coeliac disease, which has been described in three out of the 15 previously reported F-HS patients. His fac...
Citations
... For example, the "c.1843G>A; p.Gly615Arg" homozygote, "IVS1-13T>G/c.-32-13t>g" heterozygous, and "c.-1402A>T p.I468F" heterozygous were pathogenic in unrelated classical IOPD patients [12]. Pompe disease is the first having available metabolic myopathy having targeted ERT. ...
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... The results were pooled. The arrays were run according to the manufacturer's instructions at the Institute for Molecular Medicine Finland (FIMM, Helsinki, Finland) 9 and analysed with the GenomeStudio Software using the genomic build hg19. The data were filtered using PLINK (version 1.9) (zzz.bwh.harvard.edu/plink/) ...
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... The R-loop suppressing activity of TOP3B also helps during transcription in cancer cells and neuronal activity-dependent transcription in mouse brain tissue 9,10 . In parallel, TOP3B is associated with polyribosomes and translating mRNA pools, localizes to RNA stress granules (cytoplasmic membrane-less assemblies of non-translating mRNAs and proteins formed in response to cellular stress) and promotes translation of subsets of RNAs in cancer cells and neurons [5][6][7][8]11,17 . TOP3B binding also stabilizes a subset of RNAs via a topoisomerase-independent mechanism in HCT116 colon carcinoma cells 5 . ...
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... The array technique permits the assessment of the CNVs present in the whole genome of a patient in a single reaction with a high level of resolution (B0.7 kb), depending on the platform, types of probes and how they are distributed in the genome, thus increasing the detection rate of complex imbalances (4,19,20). ...
... In previous clinical studies (20,21) including our own (22), the renal ultrasound findings of NPH patients revealed normal or smaller kidneys. Histologically, corticomedullary cyst formation, atrophy of renal tubular structure, tubular basement membrane thickening or disintegration and tubulointerstitial fibrosis (TIF) are the hallmarks of NPH (23). ...
... The detection rate achieved in this study was similar to previous studies 13-28% not depending on the choice of oligonucleotide-based or SNP-based platforms 15-19%. [14][15][16][17][18][19][20] However, the smaller size CNVs identified were mostly benign. ...
... [8][9][10][11][12][13] Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene are a significant cause of infantile spasms, early epileptic seizures and of a later intractable seizures disorder. [14][15][16][17][18][19][20][21][22] Gene Features and Function CDKL5 (previous named serine/threonine kinase 9 [STK9]) is a gene encoding a serine/threonine kinase characterized by a large C-terminal and a N-terminal catalytic domain. It is located in the short arm of the X-chromosome, at position 22 (Xp22) and it was discovered in 1998. 1 CDKL5 kinase plays multiple roles and regulates distinct signaling pathways. ...
Reference: CDKL5 Gene: Beyond Rett Syndrome
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... The SCN2A gene encodes the Na V 1.2 sodium channel, which is widely expressed in the central nervous system, particularly in cortical and hippocampal glutamatergic neurons (Beckh et al., 1989;Mantegazza et al., 2021;Meisler et al., 2021). In rodents, Na V 1.2 channels are the main Na V of the AIS and the nodes of Ranvier in the first 10 days of postnatal life, then they are partially replaced by Na V 1.6 and become mainly localized to the proximal AIS (Boiko et al., 2001;Kaplan et al., 2001;Liao et al., 2010). It has been proposed that proximal Na V 1.2 channels promote backpropagation of APs to the soma (Hu et al., 2009). ...
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... CL and CP are complex multifactorial disorders, where genetic and/or environmental factors can be involved [3]. Partial autosomal deletions and duplications occur in approximately 1/7000 live birth [4]. Here we describe a further case of a de novo 20p12.3 ...
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... Goltze syndrome is a rare X-linked genetic condition caused by a mutation of the PORCN gene, of which 80 mutations have been recorded [3,4]. Its presentation can affect areas of mesodermal and ectodermal origin in multiple body systems and holds significant variation between individuals, though skin involvement is regarded as essential [1,5,6]. ...
