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D K Grange

Publications and source records attributed to D K Grange.

16 recordsLinked to original sources
PubMed2001

Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK.

Craniometaphyseal dysplasia (CMD) is a rare skeletal disorder characterized by progressive thickening and increased mineral density of craniofacial bones and abnormally developed metaphyses in long bones. Linkage studies mapped the locus for the autosomal dominant form of CMD to an approximately 5-cM interval on chromosome 5p, which is defined by recombinations between loci D5S810 and D5S1954. Mutational analysis of positional candidate genes was performed, and we describe herein three different mutations, in five different families and in isolated cases, in ANK, a multipass transmembrane protein involved in the transport of intracellular pyrophosphate into extracellular matrix. The mutations are two in-frame deletions and one in-frame insertion caused by a splicing defect. All mutations cluster within seven amino acids in one of the six possible cytosolic domains of ANK. These results suggest that the mutated protein has a dominant negative effect on the function of ANK, since reduced levels of pyrophosphate in bone matrix are known to increase mineralization.

Amino Acid Sequence↗
PubMed2001

Two unbalanced translocations involving a common 6p25 region in two XY female patients.

We report two 46,XY female patients with two different de novo unbalanced translocations, each involving the chromosomal region 6p25. The patient with a 46,XY,der(6)t(X;6)(p21.2;p25) karyotype had a sex reversal phenotype. The patient with a 46,XY,der(13)t(6;13)(p25;q33) karyotype had a male pseudohermaphrodite phenotype. Multi-paint fluorescent in situ hybridization was performed to determine the origin of the derivative material on 6p and 13q. The association of abnormalities of the 6p25 region with either an Xp duplication or a 13q deletion is reported here for the first time.

Adolescent↗
PubMed2000

Fronto-otopalatodigital osteodysplasia: clinical evidence for a single entity encompassing Melnick-Needles syndrome, otopalatodigital syndrome types 1 and 2, and frontometaphyseal dysplasia.

Otopalatodigital syndrome type 2 is an X-linked disorder with minimal expression in carrier females and comprises typical facial anomalies and a generalized bone dysplasia with osteodysplastic changes, brachydactyly, and impaired survival. Recently several other severe malformations were reported in the condition. Melnick-Needles syndrome is an X-linked dominant disorder. Affected males are usually sporadic cases. The exceptional males born to symptomatic women present with a lethal disorder comprising generalized osteodysplasia, deficiency of the first ray, and facial anomalies strikingly similar to those of otopalatodigital syndrome type 2. We report here on three boys with classical, severe, and lethal otopalatodigital type 2 syndrome, and three boys with severe (lethal) Melnick-Needles syndrome, born to affected mothers. We suggest that otopalatodigital type 1 and 2, Melnick-Needles syndrome and frontometaphyseal dysplasia, sharing many clinical manifestations and a similar mode of inheritance, are variants of the same condition: fronto-otopalatodigital osteodysplasia. The relationships to similar syndromes (i.e., Saint-Martin-Gardner-Morrisson syndrome, serpentine fibula syndrome, atelosteogenesis type 3, boomerang dysplasia, and Yunis-Varon syndrome) are discussed.

Abnormalities, Multiple↗
PubMed2000

Preferential involvement of the short arm in chromosome 8-derived supernumerary markers and ring as identified by chromosome arm painting.

We report on the use of fluorescence in situ hybridization (FISH) with specific chromosome 8 arm painting to characterize further small supernumerary chromosome 8-derived markers/rings (SMC/SRC) identified in three patients. Two patients (patients 1 and 2) who carried the marker (SMC) were evaluated because of mental retardation and minor facial anomalies. The patient (patient 3) who carried the ring (SRC) had ventriculomegaly. Parental blood chromosomes of patients 2 and 3 were normal and unavailable on patient 1. The identification of the SMC/SRC was first characterized by FISH specific alpha-repeat centromeric probes, second by FISH whole chromosome painting (WCP), and finally by FISH chromosome arm painting (CAP). The latter showed involvement of only the short arm of chromosome 8 in all three SMC/SRC cases, suggesting a U-type exchange mechanism.

Child, Preschool↗
PubMed2000

CHILD syndrome caused by deficiency of 3beta-hydroxysteroid-delta8, delta7-isomerase.

CHILD (congenital hemidysplasia, ichthyosis, and limb defects) syndrome is a rare, usually sporadic disorder associated with unilateral distribution of ichthyosiform skin lesions, limb defects, punctate calcifications of cartilaginous structures, and visceral anomalies. CHILD syndrome shares some manifestations with X-linked dominant Conradi-Hünermann syndrome (CDPX2), although the skeletal defects and skin lesions in CDPX2 are bilateral and asymmetric. Because CDPX2 patients have abnormal 8-dehydrosterol metabolism caused by mutations in 3beta-hydroxysteroid-delta8,delta7-isomerase, we measured plasma sterols in a patient with CHILD syndrome and found levels of 8-dehydrocholesterol and 8(9)-cholestenol increased to the same degree as in CDPX2 patients. Subsequently, we identified a nonsense mutation in exon 3 of the patient's 3beta-hydroxysteroid-delta8,delta7-isomerase gene. We speculate that at least some cases of CHILD syndrome are allelic with CDPX2 caused by 3beta-hydroxysteroid-delta8,delta7-isomerase deficiency.

Abnormalities, Multiple↗
PubMed1999

A patient with Ehlers-Danlos syndrome type VI is homozygous for a premature termination codon in exon 14 of the lysyl hydroxylase 1 gene.

In the present study, we have characterized a patient with Ehlers-Danlos syndrome type VI (EDS VI) as homozygous for a pathogenetic mutation in the lysyl hydroxylase 1 (LH1) gene. This mutant allele contributes to very low levels of LH1 mRNA and severely diminished LH activity in his skin fibroblasts. The reduced hydroxylysine content of collagen was reflected in the increased electrophoretic mobility of the type I collagen alpha1 and alpha2 chains precipitated from cell and media samples of cultured patient fibroblasts. The homozygous mutation, a single base change of C1557 --> G which would convert a codon for tyrosine (TAC) at residue 511 to a stop codon (TAG) in exon 14 of the LH1 gene, was identified in full-length cDNAs for LH1 amplified from the patient's fibroblasts. We have demonstrated that the low level of LH activity measured in his fibroblasts may result from a minor processing pathway in which an in-frame skipping of exon 14 containing the mutation restores partial function of the enzyme. The mutation was confirmed in both alleles in genomic DNA from the proband and by the maternal inheritance of this mutation. The father's DNA was unavailable for analysis. The autosomal recessive nature of EDS VI was verified by the fact that the mother, who has one mutated and one normal allele, is clinically unaffected by this disorder. This mutation, which has been previously observed in another unrelated compound heterozygous patient, may prove to be a more widespread mutation for EDS VI.

Adult↗
PubMed1998

Familial syndrome of progressive arterial occlusive disease consistent with fibromuscular dysplasia, hypertension, congenital cardiac defects, bone fragility, brachysyndactyly, and learning disabilities.

We report on 4 of 9 sibs with a syndrome of stenosis of the renal arteries and chronic hypertension, variable stenosis or occlusion of cerebral, abdominal and probably coronary arteries due to suspected fibromuscular dysplasia, congenital cardiac abnormalities, brachydactyly and syndactyly of the hands and feet, and increased bone fragility consistent with a mild form of osteogenesis imperfecta. Three affected individuals have had mild to moderate learning disabilities. The parents and the remaining 5 sibs have normal hands and feet and no history of excessive fractures. Individual components of this syndrome may appear as isolated conditions, including fibromuscular dysplasia, brachydactyly, syndactyly, and osteogenesis imperfecta, and are autosomal dominant traits in many cases. Explanations for this familial occurrence include autosomal recessive inheritance, autosomal dominant inheritance with decreased penetrance, or parental gonadal mosaicism for a mutation involving a single gene or several contiguous genes.

Adolescent↗
PubMed1998

Bone marrow transplantation for the treatment of alpha-mannosidosis.

We report successful bone marrow transplantation in a child with a severe form of alpha-mannosidosis, type I. There was complete resolution of the recurrent sinopulmonary disease and organomegaly, improvement in the bony disease, and stabilization of neurocognitive function.

Bone Marrow Transplantation↗
PubMed1990

Detection of point mutations in type I collagen by RNase digestion of RNA/RNA hybrids.

We have developed a strategy for the detection, localization and sequence determination of point mutations in the mRNA coding for the alpha 1(I) and alpha 2(I) chains of type I collagen. Point mutations are detected by RNase A cleavage of mismatches in RNA/RNA hybrids. The mRNAs coding for the fibrillar collagens present special problems for hybrid analysis because of their large size and their GC-rich and repetitive sequences. We have generated a series of overlapping antisense riboprobes covering the entire pro alpha 1(I) and pro alpha 2(I) mRNAs. Uniformly labelled normal antisense riboprobes are hybridized with the total fibroblast RNA of patients with possible mutations in type I collagen. Mismatches in the resulting RNA/RNA hybrids are cleaved with RNase A and the labelled riboprobe cleavage products are examined electrophoretically. The sensitivity and specificity of the system were demonstrated by the detection and localization of a known point mutation in the codon for alpha 1(I) glycine 988 (1). DNA for sequencing the mutations localized by hybrid analysis may be obtained by either (1) generation of a fibroblast cDNA library and isolation of both alleles by plaque screening, or (2) a more rapid method using first strand cDNA synthesis from poly (A+)-mRNA, followed by PCR amplification of the mutation-containing region of the DNA/RNA hybrid. This strategy for detection and isolation has wide application not only for mutations causing connective tissue disorders, but also for mutations in other large and repetitive genes. We have used this strategy for the detection and sequencing of a point mutation in alpha 2(I) mRNA associated with a case of lethal osteogenesis imperfecta. The G----A point mutation in the codon for alpha 2(I) glycine residue 805 results in the substitution of an aspartic acid at this position and is consistent with the proband's collagen protein data.

Alleles↗
PubMed1990

Analysis of cultured chorionic villi in a case of osteogenesis imperfecta type II: implications for prenatal diagnosis.

We examined collagens produced by cultured cells from skin, chorionic villi, and placental membranes of a 32 week fetus with osteogenesis imperfecta (OI) type II. We observed that skin fibroblasts synthesized two populations of pro alpha 1(I) chains of type I procollagen; one population was normal, while the other population had excessive post-translational modification. The thermal stability of helices containing the overmodified chains was reduced 1-2 degrees C. Most significantly, the cells cultured from chorionic villi produced type I collagen chains with the same electrophoretic abnormalities as the skin collagen. This suggests that chorionic villus sampling (CVS) is a means of prenatal diagnosis for families with a previous type II or type IV OI infant.

Cells, Cultured↗
PubMed1990

Rehabilitation of children and infants with osteogenesis imperfecta. A program for ambulation.

Management of children and infants with osteogenesis imperfecta (OI) poses difficult decisions for pediatricians, orthopedists, and physiatrists. These children are frequently frail with disabling bone and joint deformities and fractures. In an eight-year cumulative management of 12 children with OI, a comprehensive program included strengthening exercises to the pelvic girdle and lower extremity muscles, in addition to pool exercises and molded seating to support upright posture. Long leg braces were fitted when the children were able to sit unsupported. All 12 were fitted with braces; nine were functional ambulators, and three were home ambulators. Six children required femoral plating or rodding, two of whom subsequently had the metal removed. Lower extremity fractures averaged one and one-half per year prior to bracing for nine children who had fractures. There was 0.83 fracture per year for the ten children who had fractures after bracing. The degree of femoral bowing increased in four, decreased in four, and remained unchanged in four, while the degree of tibial bowing increased in two, decreased in nine, and remained unchanged in one during the observation period. A comprehensive rehabilitation program and long leg bracing with surgical operations on the femur result in a high level of functional activity for children with OI with an acceptable level of risk for fracture.

Braces↗
PubMed1989

Osteogenesis imperfecta type IV. Detection of a point mutation in one alpha 1(I) collagen allele (COL1A1) by RNA/RNA hybrid analysis.

We have identified a point mutation in one alpha 1(I) collagen allele (COL1A1) of a child with the type IV osteogenesis imperfecta phenotype. When compared to parental and control samples, skin fibroblasts of the proband synthesized two populations of type I collagen molecules. One population was normal; the other was delayed in secretion and electrophoretic migration due to post-translational overmodification. Two-dimensional gel electrophoresis of the CNBr peptides demonstrated a gradient of overmodification beginning near the carboxyl-terminal CB peptides. This predicts that the mutation delaying helix formation is near the carboxyl-terminal end of one of the component chains of type I collagen. The mRNA of the patient was probed with overlapping antisense riboprobes to type I collagen cDNA. Cleavage of a mismatch in RNA/RNA hybrids of RNase A allowed the location of the mutation to a 225-base pair region of alpha 1(I) cDNA. The mismatch was not present in RNA/RNA hybrids from either parent. This region of both alpha 1(I) alleles of the patient was isolated by screening a lambda ZAP cDNA library. Sequence determination of both alleles demonstrated a single nucleotide change, G----A, resulting in the substitution of a serine for a glycine at amino acid residue 832. This point mutation occurs in the coding region for alpha 1(I) CB6 and is concordant with the protein data. The finding of a glycine substitution in an alpha 1(I) chain of a patient with the milder type IV osteogenesis imperfecta phenotype requires modification of current molecular models for types II and IV osteogenesis imperfecta.

Alleles↗
PubMedDate not supplied

Nutritional vitamin B12 deficiency in a breastfed infant following maternal gastric bypass.

Breastfed infants of women who have had gastric or intestinal bypass procedures may develop nutritional deficiencies. We describe a 10-month-old exclusively breastfed white male infant who presented with vomiting, failure to thrive, and megaloblastic anemia. He was found to have vitamin B12 deficiency. His mother had undergone a gastric bypass procedure for morbid obesity 2 years prior to her pregnancy with this child. She had subclinical vitamin B12 deficiency, with an abnormal Schilling test that corrected with the addition of intrinsic factor. Therefore, we believe that the mother's gastric bypass had caused a decrease in available intrinsic factor, resulting in subclinical vitamin B12 deficiency and decreased breast milk B12. Although she was asymptomatic, her breastfed infant developed symptomatic B12 deficiency. This is the first reported case of a maternal gastric bypass resulting in vitamin B12 deficiency in an infant. These mothers should receive vitamin supplements, including vitamin B12, during and after pregnancy, and may require parenterally administered vitamin B12.

Adult↗