Riitta Herva

Positionally Cloned Gene for a Novel Glomerular Protein—Nephrin—Is Mutated in Congenital Nephrotic Syndrome

Congenital nephrotic syndrome of the Finnish type (NPHS1) is an autosomal-recessive disorder, characterized by massive proteinuria in utero and nephrosis at birth. In this study, the 150 kb critical region of NPHS1 was sequenced, revealing the presence of at least 11 genes, the structures of 5 of which were determined. Four different mutations segregating with the disease were found in one of the genes in NPHS1 patients. The NPHS1 gene product, termed nephrin, is a 1241-residue putative transmembrane protein of the immunoglobulin family of cell adhesion molecules, which by Northern and in situ hybridization was shown to be specifically expressed in renal glomeruli. The results demonstrate a crucial role for this protein in the development or function of the kidney filtration barrier.

Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.

Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis1,2,3. We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3–q43 (refs 4–6). Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. Leiomyomatosis-associated mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Activity of fumarate hydratase is reduced in lymphoblastoid cells from individuals with leiomyomatosis. This enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity is very low or absent in tumors from individuals with leiomyomatosis. Mutations in FH also occur in the recessive condition fumarate hydratase deficiency7,8,9,10,11, and some parents of people with this condition are susceptible to leiomyomata. Thus, heterozygous and homozygous or compound heterozygous mutants have very different clinical phenotypes. Our results provide clues to the pathogenesis of fibroids and emphasize the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumor12,13,14.Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis. We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3–q43 (refs 4–6). Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. Leiomyomatosis-associated mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Activity of fumarate hydratase is reduced in lymphoblastoid cells from individuals with leiomyomatosis. This enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity is very low or absent in tumors from individuals with leiomyomatosis. Mutations in FH also occur in the recessive condition fumarate hydratase deficiency, and some parents of people with this condition are susceptible to leiomyomata. Thus, heterozygous and homozygous or compound heterozygous mutants have very different clinical phenotypes. Our results provide clues to the pathogenesis of fibroids and emphasize the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumor.

Inherited susceptibility to uterine leiomyomas and renal cell cancer

Herein we report the clinical, histopathological, and molecular features of a cancer syndrome with predisposition to uterine leiomyomas and papillary renal cell carcinoma. The studied kindred included 11 family members with uterine leiomyomas and two with uterine leiomyosarcoma. Seven individuals had a history of cutaneous nodules, two of which were confirmed to be cutaneous leiomyomatosis. The four kidney cancer cases occurred in young (33- to 48-year-old) females and displayed a unique natural history. All these kidney cancers displayed a distinct papillary histology and presented as unilateral solitary lesions that had metastasized at the time of diagnosis. Genetic-marker analysis mapped the predisposition gene to chromosome 1q. Losses of the normal chromosome 1q were observed in tumors that had occurred in the kindred, including a uterine leiomyoma. Moreover, the observed histological features were used as a tool to diagnose a second kindred displaying the phenotype. We have shown that predisposition to uterine leiomyomas and papillary renal cell cancer can be inherited dominantly through the hereditary leiomyomatosis and renal cell cancer (HLRCC) gene. The HLRCC gene maps to chromosome 1q and is likely to be a tumor suppressor. Clinical, histopathological, and molecular tools are now available for accurate detection and diagnosis of this cancer syndrome.

A deletion in chromosome 22 can cause DiGeorge syndrome.

SummaryAn association between DiGeorges syndrome and an unbalanced chromosomal rearrangement leading to trisomy 20pter→20q11 and monosomy 22pter→22q11 was found in four individuals belonging to one family. These and other data from the literature are interpreted to suggest that DiGeorges syndrome can be caused by deletion of a gene located in chromosome 22, probably in band 22q11.

Early-Onset Renal Cell Carcinoma as a Novel Extraparaganglial Component of SDHB-Associated Heritable Paraganglioma

Hereditary paraganglioma syndrome has recently been shown to be caused by germline heterozygous mutations in three (SDHB, SDHC, and SDHD) of the four genes that encode mitochondrial succinate dehydrogenase. Extraparaganglial component neoplasias have never been previously documented. In a population-based registry of symptomatic presentations of phaeochromocytoma/paraganglioma comprising 352 registrants, among whom 16 unrelated registrants were SDHB mutation positive, one family with germline SDHB mutation c.847-50delTCTC had two members with renal cell carcinoma (RCC), of solid histology, at ages 24 and 26 years. Both also had paraganglioma. A registry of early-onset RCCs revealed a family comprising a son with clear-cell RCC and his mother with a cardiac tumor, both with the germline SDHB R27X mutation. The cardiac tumor proved to be a paraganglioma. All RCCs showed loss of the remaining wild-type allele. Our observations suggest that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas and carry implications for medical surveillance.

Collagenase-3 (MMP-13) is expressed by hypertrophic chondrocytes, periosteal cells, and osteoblasts during human fetal bone development.

Collagenase‐3 (MMP‐13) is a novel matrix metalloproteinase, the expression of which has so far only been documented in human breast carcinomas and osteoarthritic cartilage. In this study we have examined the expression of MMP‐13 during human fetal development. Northern blot hybridizations revealed abundant expression of MMP‐13 mRNAs in total RNA from fetal cartilage and calvaria at gestational age of 15 weeks. By in situ hybridization MMP‐13 transcripts were detected in chondrocytes of hypertrophic cartilage in vertebrae of the spinal column and in the dorsal end of ribs undergoing ossification, as well as in osteoblasts and periosteal cells below the inner periosteal region of ossified ribs. In contrast, no expression of MMP‐13 could be detected in osteoclasts. Furthermore, expression of MMP‐13 mRNA was detected in osteoblasts and fibroblasts primarily on the inner side of calvarial bone of the skull at 16 weeks of gestation. Expression of MMP‐13 mRNA by primary human fetal chondrocytes in culture was enhanced by transforming growth factor‐β (TGF‐β) and inhibited by bone morphogenetic protein‐2 (BMP‐2). No expression of MMP‐13 mRNA could be noted in other fetal tissues, including the skin, lungs, neural tissue, muscle, and liver. These results suggest that MMP‐13 plays an important role in the extracellular matrix remodeling during fetal bone development both via endochondral and intramembranous ossification. Dev. Dyn. 208:387–395, 1997.

Familial Cutaneous Leiomyomatosis Is a Two-Hit Condition Associated with Renal Cell Cancer of Characteristic Histopathology

Little has been known about the molecular background of familial multiple cutaneous leiomyomatosis (MCL). We report here a clinical, histopathological, and molecular study of a multiple cutaneous leiomyomatosis kindred with seven affected members. This detailed study revealed strong features of a recently described cancer predisposition syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC). The family was compatible with linkage to the HLRCC locus in 1q. Also, all seven cutaneous leiomyomas derived from the proband and analyzed for loss of heterozygosity displayed loss of the wild-type allele, confirming the association with a susceptibility gene in chromosome 1q. One individual had had renal cell cancer at the age of 35 years. This tumor displayed a rare papillary histopathology, which appears to be characteristic for HLRCC. The derived linkage, loss of heterozygosity, and clinical data suggest that MCL and HLRCC are a single disease with a variable phenotype. The possibility that members of leiomyomatosis families are predisposed to renal cell cancer should be taken into account.

Population cohort associating chorioamnionitis, cord inflammatory cytokines and neurologic outcome in very preterm, extremely low birth weight infants.

Intrauterine inflammation may relate to neurologic disability among preterm children. We investigated the relationship between chorioamnionitis, cord serum cytokines, and neurologic outcome. Sixty-one consecutively born very preterm extremely low birth weight (ELBW) infants were prospectively enrolled. Histologic inflammation in placenta and umbilical cord and vascular pathology were evaluated. Cord sera were analyzed for five proinflammatory cytokines. Serial brain ultrasound and magnetic resonance imaging were performed for evaluation of intraventricular hemorrhage (IVH grade I–III) and white matter damage (WMD: cystic periventricular leukomalacia or IVH grade IV). Neurologic and neurocognitive outcomes were assessed at the corrected age of 2 y. The incidences of HCA, WMD, and abnormal neurologic outcome were 48%, 13% and 19%, respectively. HCA or high IL-6 in cord serum predicted spontaneous preterm labor with high accuracy. HCA increased the risk of IVH grade II-III. In HCA, without either clinical chorioamnionitis or histologic placental perfusion defect, the children had a low risk of WMD (0%) and a low risk of abnormal neurologic outcome (6%). In HCA, the concentration of IL-6 in cord serum was lower in children with abnormal neurologic outcome than in children with normal neurologic outcome. In HCA and placental perfusion defect (compound defect) the risk of abnormal neurologic outcome was high. Compound placental defect and WMD additively predicted abnormal neurologic outcome. We propose that HCA together with other insults (placental perfusion defect or maternal systemic infection) increases the risk of poor neurologic outcome in very preterm ELBW infants.

Increased risk of cancer in patients with fumarate hydratase germline mutation

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. The condition is characterised by predisposition to benign leiomyomas of the skin and the uterus, renal cell carcinoma (RCC), and uterine leiomyosarcoma (ULMS). To comprehensively examine the cancer risk and tumour spectrum in Finnish FH mutation positive families, genealogical and cancer data were obtained from 868 individuals. The cohort analysis of the standardised incidence ratios (SIR) was analysed from 256 individuals. FH mutation status was analysed from all available individuals (n = 98). To study tumour spectrum in FH mutation carriers, loss of the wild type allele was analysed from all available tumours (n = 22). The SIR was 6.5 for RCC and 71 for ULMS. The overall cancer risk was statistically significantly increased in the age group of 15–29 years, consistent with features of cancer predisposition families in general. FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS tumours displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, several benign tumours including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas were observed. The present study confirms with calculated risk ratios the association of early onset RCC and ULMS with FH germline mutations in Finns. Some evidence for association of breast and bladder carcinoma with HLRCC was obtained. The data enlighten the organ specific malignant potential of HLRCC.

Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease

The most severe forms of motoneuron disease manifest in utero are characterized by marked atrophy of spinal cord motoneurons and fetal immobility. Here, we report that the defective gene underlying lethal motoneuron syndrome LCCS1 is the mRNA export mediator GLE1. Our finding of mutated GLE1 exposes a common pathway connecting the genes implicated in LCCS1, LCCS2 and LCCS3 and elucidates mRNA processing as a critical molecular mechanism in motoneuron development and maturation.