Mutations in DHDPSL are responsible for primary hyperoxaluria type III.

Primary hyperoxaluria (PH) is an autosomal-recessive disorder of endogenous oxalate synthesis characterized by accumulation of calcium oxalate primarily in the kidney. Deficiencies of alanine-glyoxylate aminotransferase (AGT) or glyoxylate reductase (GRHPR) are the two known causes of the disease (PH I and II, respectively). To determine the etiology of an as yet uncharacterized type of PH, we selected a cohort of 15 non-PH I/PH II patients from eight unrelated families with calcium oxalate nephrolithiasis for high-density SNP microarray analysis. We determined that mutations in an uncharacterized gene, DHDPSL, on chromosome 10 cause a third type of PH (PH III). To overcome the difficulties in data analysis attributed to a state of compound heterozygosity, we developed a strategy of "heterozygosity mapping"-a search for long heterozygous patterns unique to all patients in a given family and overlapping between families, followed by reconstruction of haplotypes. This approach enabled us to determine an allelic fragment shared by all patients of Ashkenazi Jewish descent and bearing a 3 bp deletion in DHDPSL. Overall, six mutations were detected: four missense mutations, one in-frame deletion, and one splice-site mutation. Our assumption is that DHDPSL is the gene encoding 4-hydroxy-2-oxoglutarate aldolase, catalyzing the final step in the metabolic pathway of hydroxyproline.

Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3.

Distal myopathies represent a heterogeneous group of inherited skeletal muscle disorders. One type of adult-onset, progressive autosomal-dominant distal myopathy, frequently associated with dysphagia and dysphonia (vocal cord and pharyngeal weakness with distal myopathy [VCPDM]), has been mapped to chromosome 5q31 in a North American pedigree. Here, we report the identification of a second large VCPDM family of Bulgarian descent and fine mapping of the critical interval. Sequencing of positional candidate genes revealed precisely the same nonconservative S85C missense mutation affecting an interspecies conserved residue in the MATR3 gene in both families. MATR3 is expressed in skeletal muscle and encodes matrin 3, a component of the nuclear matrix, which is a proteinaceous network that extends throughout the nucleus. Different disease related haplotype signatures in the two families provided evidence that two independent mutational events at the same position in MATR3 cause VCPDM. Our data establish proof of principle that the nuclear matrix is crucial for normal skeletal muscle structure and function and put VCPDM on the growing list of monogenic disorders associated with the nuclear proteome.

Myotilin is not the causative gene for vocal cord and pharyngeal weakness with distal myopathy (VCPDM).

Myotilin (MYOT) is a promising candidate gene for Vocal Cord and Pharyngeal Weakness with Distal Myopathy (VCPDM, also known as MPD2). Located within the minimum VCPDM candidate interval, myotilin mutations also cause a similarly progressive and adult-onset muscle disease. We examined myotilin in VCPDM patients by sequence analysis, RT-PCR, Southern blotting, and western blotting. We detected no defects in the myotilin gene, transcript, or protein in VCPDM. We also report several useful SNPs and STRs for the analysis of myotilin in muscle diseases of suspected, yet unknown genetic origin. We conclude that MYOT mutations likely are not a cause of VCPDM.

Amish brittle hair syndrome gene maps to 7p14.1.

The brittle hair syndrome (BHS) is characterized by short stature, intellectual impairment, brittle hair, and decreased fertility in 20 members from a large Amish consanguineous kindred previously reported affected with this syndrome. We mapped the BHS gene by genome scan to chromosome 7p14.1. Evidence of linkage was supported by a maximum multipoint LOD score of 6 obtained with GENEHUNTER for the linkage interval defined by markers D7S484-D7S2422 distant by 17.2 cM. Two-point linkage analysis performed with SUPERLINK yielded a LOD score of 9.02 at theta = 0 for marker D7S2497 located within that interval. Analysis of haplotypes homozygous-by-descent allowed fine mapping of the BHS gene within a 4.81 cM interval delimited by markers D7S2497 and D7S691, a region that spreads over 3.42 Mb.

Identification of C7orf11 (TTDN1) gene mutations and genetic heterogeneity in nonphotosensitive trichothiodystrophy.

We have identified C7orf11, which localizes to the nucleus and is expressed in fetal hair follicles, as the first disease gene for nonphotosensitive trichothiodystrophy (TTD). C7orf11 maps to chromosome 7p14, and the disease locus has been designated "TTDN1" (TTD nonphotosensitive 1). Mutations were found in patients with Amish brittle-hair syndrome and in other nonphotosensititive TTD cases with mental retardation and decreased fertility but not in patients with Sabinas syndrome or Pollitt syndrome. Therefore, genetic heterogeneity in nonphotosensitive TTD is a feature similar to that observed in photosensitive TTD, which is caused by mutations in transcription factor II H (TFIIH) subunit genes. Comparative immunofluorescence analysis, however, suggests that C7orf11 does not influence TFIIH directly. Given the absence of cutaneous photosensitivity in the patients with C7orf11 mutations, together with the protein's nuclear localization, C7orf11 may be involved in transcription but not DNA repair.