Sabine Rudnik-Schöneborn

PKHD1, the Polycystic Kidney and Hepatic Disease 1 Gene, Encodes a Novel Large Protein Containing Multiple Immunoglobulin-Like Plexin-Transcription–Factor Domains and Parallel Beta-Helix 1 Repeats

Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of polycystic kidney disease that presents primarily in infancy and childhood and that is characterized by enlarged kidneys and congenital hepatic fibrosis. We have identified PKHD1, the gene mutated in ARPKD. PKHD1 extends over > or =469 kb, is primarily expressed in human fetal and adult kidney, and includes a minimum of 86 exons that are variably assembled into a number of alternatively spliced transcripts. The longest continuous open reading frame encodes a 4,074-amino-acid protein, polyductin, that is predicted to have a single transmembrane (TM)-spanning domain near its carboxyl terminus, immunoglobulin-like plexin-transcription-factor domains, and parallel beta-helix 1 repeats in its amino terminus. Several transcripts encode truncated products that lack the TM and that may be secreted if translated. The PKHD1-gene products are members of a novel class of proteins that share structural features with hepatocyte growth-factor receptor and plexins and that belong to a superfamily of proteins involved in regulation of cell proliferation and of cellular adhesion and repulsion.

Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling.

Problems with diagnosis and genetic counseling occur for patients with autosomal recessive proximal spinal muscular atrophy (SMA) who do not show the most common mutation: homozygous absence of at least exon 7 of the telomeric survival motor neuron gene (SMN1). Here we present molecular genetic data for 42 independent nondeleted SMA patients. A nonradioactive quantitative PCR test showed one SMN1 copy in 19 patients (45%). By sequencing cloned reverse-transcription (RT) PCR products or genomic fragments of SMN1, we identified nine different mutations in 18 of the 19 patients, six described for the first time: three missense mutations (Y272C, T274I, S262I), three frameshift mutations in exons 2a, 2b, and 4 (124insT, 241-242ins4, 591delA), one nonsense mutation in exon 1 (Q15X), one Alu-mediated deletion from intron 4 to intron 6, and one donor splice site mutation in intron 7 (c.922+6T-->G). The most frequent mutation, Y272C, was found in 6 (33%) of 18 patients. Each intragenic mutation found in at least two patients occurred on the same haplotype background, indicating founder mutations. Genotype-phenotype correlation allowed inference of the effect of each mutation on the function of the SMN1 protein and the role of the SMN2 copy number in modulating the SMA phenotype. In 14 of 23 SMA patients with two SMN1 copies, at least one intact SMN1 copy was sequenced, which excludes a 5q-SMA and suggests the existence of further gene(s) responsible for approximately 4%-5% of phenotypes indistinguishable from SMA. We determined the validity of the test, and we discuss its practical implications and limitations.

Mutations in the gene encoding immunoglobulin μ-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1

Classic spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of SMN1. Its product is involved in various cellular processes, including cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins, pre-mRNA processing and activation of transcription. Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct from SMA. Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin μ-binding protein 2 (IGHMBP2; on chromosome 11q13.2–q13.4). In six SMARD1 families, we detected three recessive missense mutations (exons 5, 11 and 12), two nonsense mutations (exons 2 and 5), one frameshift deletion (exon 5) and one splice donor-site mutation (intron 13). Mutations in mouse Ighmbp2 (ref. 14) have been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (nmd) mouse, whose phenotype resembles the SMARD1 phenotype. Like the SMN1 product, IGHMBP2 colocalizes with the RNA-processing machinery in both the cytoplasm and the nucleus. Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals.

Mutations in SIL1 cause Marinesco-Sjogren syndrome, a cerebellar ataxia with cataract and myopathy

SIL1 (also called BAP) acts as a nucleotide exchange factor for the Hsp70 chaperone BiP (also called GRP78), which is a key regulator of the main functions of the endoplasmic reticulum. We found nine distinct mutations that would disrupt the SIL1 protein in individuals with Marinesco-Sjögren syndrome, an autosomal recessive cerebellar ataxia complicated by cataracts, developmental delay and myopathy. Identification of SIL1 mutations implicates Marinesco-Sjögren syndrome as a disease of endoplasmic reticulum dysfunction and suggests a role for this organelle in multisystem disorders.

Mutations in a Gene Encoding a Novel SH3/TPR Domain Protein Cause Autosomal Recessive Charcot-Marie-Tooth Type 4C Neuropathy

Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR domains that are likely involved in the formation of protein complexes.

Congenital heart disease is a feature of severe infantile spinal muscular atrophy

Objective: Homozygous deletions/mutations of the SMN1 gene cause infantile spinal muscular atrophy (SMA). The presence of at least one SMN2 gene copy is required for normal embryogenesis. Lack of SMN protein results in degeneration of motor neurons, while extraneuronal manifestations have been regarded as a chance association with SMA. We report on heart defects in the subgroup of congenital SMA type I patients. Methods: Data were recruited from 65 unselected SMA I patients whose diagnosis had been confirmed genetically within the first 6 months of age. SMN2 copy numbers were analysed retrospectively and correlated with clinical findings including heart malformations. Results: Four (6%) patients had one copy of SMN2, 56 (86%) had two and five (8%) had three SMN2 copies. Three out of four (75%) patients with a single SMN2 copy had congenital SMA with haemodynamically relevant atrial or ventricular septal defects. Conclusions: Previous case reports of SMA I patients with congenital heart defects did not clarify whether the cardiac malformations were coincidental. Given the respective incidences of congenitally lethal SMA with a single SMN2 copy and of cardiac septal defects in humans, a chance association of both conditions would occur in less than one out of 50 million individuals. Our findings suggest that the SMN protein is relevant for normal cardiogenesis.

Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.

A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients

We analyzed clinical data of 569 patients in two combined series with childhood and juvenile proximal SMA. This cohort included only patients who had achieved the ability to sit unaided (type II and III SMA). The survival rate among 240 type II patients (who sat but never walked) was 98.5% at 5 years and 68.5% at 25 years. SMA III (n = 329) (those who walked and had symptoms before age 30 years) was subdivided into those with an onset before and after age 3 years (type IIIa, n = 195; SMA IIIb, n = 134). In patients with SMA III, life expectancy is not significantly less than a normal population. The probabilities of being able to walk at 10 years after onset was 70.3%, and at 40 years, 22.0% in SMA IIa. For SMA IIIb, 96.7% were walking 10 years after onset and 58.7% at 40 years. The subdivision of type III SMA was justified by the probability of being ambulatory depending on age at onset; the prognosis differed for those with onset before or after age 3 years. The data provide a reliable basis of the natural history of proximal SMA and support a classification system that is based primarily on age at onset and the achievement of motor milestones.

Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1)

Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1) is the second anterior horn cell disease in infants in which the genetic defect has been defined. SMARD1 results from mutations in the gene encoding the immunoglobulin μ‐binding protein 2 (IGHMBP2) on chromosome 11q13. Our aim was to review the clinical features of 29 infants affected with SMARD1 and report on 26 novel IGHMBP2 mutations. Intrauterine growth retardation, weak cry, and foot deformities were the earliest symptoms of SMARD1. Most patients presented at the age of 1 to 6 months with respiratory distress due to diaphragmatic paralysis and progressive muscle weakness with predominantly distal lower limb muscle involvement. Sensory and autonomic nerves are also affected. Because of the poor prognosis, there is a demand for prenatal diagnosis, and clear diagnostic criteria for infantile SMARD1 are needed. The diagnosis of SMARD1 should be considered in infants with non‐5q spinal muscular atrophy, neuropathy, and muscle weakness and/or respiratory distress of unclear cause. Furthermore, consanguineous parents of a child with sudden infant death syndrome should be examined for IGHMBP2 mutations.

Genes and the preeclampsia syndrome.

Abstract Preeclampsia is specific to pregnancy and is still a leading cause of maternal and perinatal mortality and morbidity, affecting about 3% of women, but the underlying pathogenetic mechanisms still remain unclear. Immune maladaptation, placental ischemia and increased oxidative stress represent the main components discussed to be of etiologic importance, and they all may have genetic implications. Since the familial nature of preeclampsia is known for many years, extensive research on the genetic contribution to the pathogenesis of this severe pregnancy disorder has been performed. In this review, we will overview the linkage and candidate gene studies carried out so far as well as summarize important historical notes on the genetic hypotheses generated in preeclampsia research. Moreover, the influence of maternal and fetal genes and their interaction as well as the role of genomic imprinting in preeclampsia will be discussed.